Guanidine compound

ABSTRACT

[Problem] 
     The present invention provides a compound which is useful as an active ingredient of a pharmaceutical composition, in particular, a pharmaceutical composition for preventing and/or treating VAP-1-related diseases. 
     [Means for Solution] 
     The present inventors have conducted intensive studies on a compound having a VAP-1 inhibitory activity, and as a result, they have found that the compound or a salt thereof of the present invention exhibits an excellent VAP-1 inhibitory activity and is useful for preventing and/or treating VAP-1-related diseases, in particular, diabetic nephropathy or diabetic macular edema, thereby completing the present invention. In addition, the present invention relates to a pharmaceutical composition, in particular, a pharmaceutical composition for preventing and/or treating VAP-1-related diseases, which comprises the compound or a salt thereof of the present invention, and an excipient.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation application of U.S.application Ser. No. 13/755,822, filed Jan. 31, 2013, which is acontinuation-in-part of PCT/JP2012/056429, filed Mar. 13, 2012, andclaims priority to JP 2011-056031, filed Mar. 15, 2011.

TECHNICAL FIELD

The present invention relates to a guanidine compound which is useful asan active ingredient of a pharmaceutical composition, in particular, apharmaceutical composition for preventing and/or treating vascularadhesion protein-1 (hereinafter abbreviated as VAP-1)-related diseases.

BACKGROUND ART

VAP-1 is an amine oxidase (semicarbazide-sensitive amine oxidase, SSAO)which is abundant in human plasma (Non-Patent Document 1), and showsremarkably increased expression in vascular endothelium and vascularsmooth muscle of inflammatory regions. While the physiological role ofVAP-1 has not been clarified until recently, VAP-1 gene was cloned in1998, and VAP-1 has been reported to be a membrane protein thatregulates rolling and migration of lymphocytes and NK cells as anadhesion molecule under regulation of expression by inflammatorycytokines. Although the amine acting as a substrate is unknown, it isconsidered to be methylamine generated in any part of a living body. Itis also known that hydrogen peroxide and aldehydes produced due to theamine oxidase activity in the molecule are important factors of adhesionactivity.

A recent report has demonstrated that the VAP-1 enzyme activity inplasma increases in patients with diabetes mellitus, whether type I ortype II, and the increase is particularly remarkable in patients withdiabetes mellitus suffering from retinopathy complications (Non-PatentDocuments 2 and 3).

In addition, it has been reported that VAP-1 is related to the followingdiseases:

(1) cirrhosis, essential stabilized hypertension, diabetes mellitus, andarthrosis (Patent Documents 1 and 2);

(2) endothelium damage (in diabetes mellitus, arterosclerosis, andhypertension), cardiovascular diseases related to diabetes mellitus anduremia, pain related to gout and arthritis, and retinopathy (in diabetesmellitus patients) (Patent Document 3);

(3) inflammatory diseases or conditions (of connective tissue)(rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis andosteoarthritis or degenerative joint disease, Reiter's syndrome,Sjogren's syndrome, Behcet's syndrome, relapsing polychondritis,systemic lupus erythematosus, discoid lupus erythematosus, systemicsclerosis, eosinophilic fasciitis, polymyositis, dermatomyositis,polymyalgia rheumatica, vasculitis, temporal arteritis, polyarteritisnodosa, Wegener's granulomatosis, mixed connective tissue disease, andjuvenile rheumatoid arthritis); gastrointestinal inflammatory diseasesor conditions [Crohn's disease, ulcerative colitis, irritable bowelsyndrome (spastic colon), fibrotic conditions of the liver, inflammationof the oral mucosa (stomatitis), and recurrent aphtous stomatitis];central nervous system inflammatory diseases or conditions (multiplesclerosis, Alzheimer's disease, and ischemia-reperfusion injury relatedto ischemic stroke); pulmonary inflammatory diseases or conditions(asthma, adult respiratory distress syndrome, and chronic obstructivepulmonary disease); (chronic) skin inflammatory diseases or conditions(psoriasis, allergic lesions, lichen planus, pityriasis rosea, contactdermatitis, atopic dermatitis, and pityriasis rubra pilaris); diseasesrelated to carbohydrate metabolism (diabetes mellitus and complicationsfrom diabetes mellitus) including microvascular and macrovasculardiseases (arterosclerosis, vascular retinopathies, retinopathy,nephropathy, nephrotic syndrome and neuropathy (polyneuropathy,mononeuropathies and autonomic neuropathy), foot ulcers, joint problems,and increased risk of infection); diseases related to aberrations inadipocyte differentiation or function or smooth muscle cell function(arterosclerosis and obesity); vascular diseases [atheromatousarterosclerosis, nonatheromatous arterosclerosis, ischemic heart diseaseincluding myocardial infarction and peripheral arterial occlusion,Raynaud's disease and phenomenon, and thromboangiitis obliterans(Buerger's disease)]; chronic arthritis; inflammatory bowel diseases;and skin dermatoses (Patent Documents 4, 5, and 6, and Non-PatentDocuments 4 and 5);

(4) diabetes mellitus (Patent Document 7);

(5) SSAO-mediated complications [diabetes mellitus (insulin dependentdiabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus(NIDDM)) and vascular complications (heart attack, angina, strokes,amputations, blindness, and renal insufficiency)], and macular edema(for example, diabetic and non-diabetic macular edema) (Patent Documents8 and 9); and

(6) hepatitis, transplantation, and the like.

Accordingly, the compounds acting on a VAP-1 enzyme may be used as anagent for preventing and/or treating the above-described diseases.

On the other hand, in Patent Document 9, it is disclosed that a compoundrepresented by the formula (A) has a VAP-1 inhibitory activity.

(wherein Z represents

For the other symbols in the formula, refer to the corresponding patentpublications)

Further, in Patent Document 10, it is disclosed that a compoundrepresented by the formula (B) has a VAP-1 inhibitory activity.

(For the symbols in the formula, refer to the corresponding patentpublications)

In Patent Document 11, it is disclosed that a compound represented bythe formula (C) has a VAP-1 inhibitory activity and is effective inapplications for treatment of VAP-1-related diseases, in particular,macular edema.

(wherein Z represents

For the other symbols in the formula, refer to the corresponding patentpublications)

In addition, in Patent Document 12, it is disclosed that a compoundrepresented by the formula (D) has a VAP-1 inhibitory activity.

(wherein

D represents —NR³ and E represents amino which may be substituted(optionally substituted amino), for the other symbols, refer to thecorresponding patent publications)

In Patent Document 13, it is disclosed that a compound represented bythe formula (E) has a VAP-1 inhibitory activity.

(wherein

X represents a divalent residue derived from thiazole which may besubstituted (divalent residue derived from optionally substitutedthiazole),

Z represents A-B-D-E, A represents a divalent residue derived frombenzene which may be substituted (divalent residue derived fromoptionally substituted benzene) or a divalent residue derived fromthiophene which may be substituted (divalent residue derived fromoptionally substituted thiophene), B represents —(CH₂)_(l)—NR²—CO—, Drepresents —NR³, and E represents amino which may be substituted(optionally substituted amino), for the other symbols, refer to thecorresponding patent publications)

In Patent Document 14, it is disclosed that a compound represented bythe formula (F) has a GPR119 agonistic activity, and is thus useful for,for example, treatment of diabetes mellitus or the like.

(For the symbols in the formula, refer to the corresponding patentpublications)

In Patent Document 15, it is disclosed that a compound represented bythe formula (G) has a GPR119 agonistic activity, and is thus useful for,for example, treatment of diabetes mellitus or the like.

(For the symbols in the formula, refer to the corresponding patentpublications)

In Patent Document 16, which is a patent application published after thefiling date of the application which forms the basis of the priority ofthe present application, it is disclosed that a compound represented bythe formula (H) has a VAP-1 activity.

RELATED ART Patent Document

Patent Document 1: JP-A-61-239891

Patent Document 2: U.S. Pat. No. 4,888,283

Patent Document 3: Pamphlet of International Publication WO 93/23023

Patent Document 4: Pamphlet of International Publication WO 02/02090

Patent Document 5: Pamphlet of International Publication WO 02/02541

Patent Document 6: US Patent Application Publication No. 2002/0173521

Patent Document 7: Pamphlet of International Publication WO 02/38152

Patent Document 8: Pamphlet of International Publication WO 02/38153

Patent Document 9: Pamphlet of International Publication WO 04/067521

Patent Document 10: Pamphlet of International Publication WO 06/011631

Patent Document 11: Pamphlet of International Publication WO 04/087138

Patent Document 12: Pamphlet of International Publication WO 09/145360

Patent Document 13: Pamphlet of International Publication WO 09/096609

Patent Document 14: Pamphlet of International Publication WO 08/025800

Patent Document 15: Pamphlet of International Publication WO 08/070692

Patent Document 16: Pamphlet of International Publication WO 11/034078

Non-Patent Document

Non-Patent Document 1: J Neural Transm, Vol. 114, pp. 747-749, 2007

Non-Patent Document 2: Diabetologia, Vol. 42, pp. 233-237, 1999

Non-Patent Document 3: Diabetic Medicine, Vol. 16, pp. 514-521, 1999

Non-Patent Document 4: Diabetologia, Vol. 40, pp. 1243-1250, 1997

Non-Patent Document 5: J Neural Transm, Vol. 114, pp. 841-843, 2007

DISCLOSURE OF INVENTION Problems to be Solved by the Invention

The present invention provides a compound which is useful as an activeingredient of a pharmaceutical composition, in particular, apharmaceutical composition for preventing and/or treating VAP-1-relateddiseases.

Means for Solving the Problems

The present inventors have conducted intensive studies on a compoundhaving a VAP-1 inhibitory activity, and as a result, they have foundthat a compound of the formula (I) or a salt thereof exhibits anexcellent VAP-1 inhibitory activity and is useful for preventing and/ortreating VAP-1-related diseases, in particular, diabetic nephropathy ordiabetic macular edema, thereby completing the present invention.

That is, the present invention relates to a compound of the formula (I)or a salt thereof and a pharmaceutical composition comprising thecompound of the formula (I) or a salt thereof and an excipient.

(wherein

A is aryl which may be substituted, or a hetero ring group which may besubstituted,

R¹, R², R³ and R⁴ are the same as or different from each other, and areH, halogen, or lower alkyl which may be substituted,

E is a single bond, or lower alkylene which may be substituted,

G is a single bond, O, NH, or N(lower alkyl which may be substituted),

J is a single bond, or lower alkylene which may be substituted,

L is O, NH, or N(lower alkyl which may be substituted),

U is a single bond, O, NH, N(lower alkyl which may be substituted), SO₂,or lower alkylene which may be substituted,

V is a single bond, O, NH, N(lower alkyl which may be substituted), orlower alkylene which may be substituted,

W is a single bond, SO, SO₂, or lower alkylene which may be substituted,

X is H, OH, NH₂, lower alkyl which may be substituted, O-(lower alkylwhich may be substituted), NH(lower alkyl which may be substituted),N(lower alkyl which may be substituted)₂, NH—SO₂-(lower alkyl which maybe substituted), N(lower alkyl which may be substituted)-SO₂-(loweralkyl which may be substituted), cycloalkyl which may be substituted,O-(cycloalkyl which may be substituted), cycloalkenyl which may besubstituted, aryl which may be substituted, O-(aryl which may besubstituted), a hetero ring group which may be substituted, or O-(heteroring group which may be substituted).)

Furthermore, unless specified otherwise, in the case where the symbolsof the chemical formulae in the present specification are also used inother chemical formulae, the same symbols denote the same meanings.

The present invention relates to a pharmaceutical composition comprisingthe compound of the formula (I) or a salt thereof, and an excipient.

Furthermore, the present invention relates to a pharmaceuticalcomposition, in particular, a pharmaceutical composition for preventingand/or treating VAP-1-related diseases, which comprises the compound ofthe formula (I) or a salt thereof, and an excipient.

In addition, the present invention relates to use of the compound of theformula (I) or a salt thereof for the manufacture of a pharmaceuticalcomposition for preventing and/or treating VAP-1-related diseases, useof the compound of the formula (I) or a salt thereof for preventingand/or treating VAP-1-related diseases, the compound of the formula (I)or a salt thereof for preventing and/or treating VAP-1-related diseases,and a method for preventing and/or treating VAP-1-related diseases,comprising administering to a patient an effective amount of thecompound of the formula (I) or a salt thereof.

Effects of the Invention

The compound of the formula (I) or a salt thereof has a VAP-1 inhibitoryaction, and can be used as an agent for preventing and/or treatingVAP-1-related diseases.

Further, the VAP-1-related diseases refer to diseases selected from thegroup consisting of:

(1) cirrhosis, essential stabilized hypertension, diabetes mellitus, andarthrosis;

(2) endothelium damage (in diabetes mellitus, arterosclerosis, andhypertension), cardiovascular diseases related to diabetes mellitus anduremia, pain related to gout and arthritis, and retinopathy (in diabetesmellitus patients);

(3) (connective tissue) inflammatory diseases or conditions (rheumatoidarthritis, ankylosing spondylitis, psoriatic arthritis andosteoarthritis or degenerative joint disease, Reiter's syndrome,Sjogren's syndrome, Behcet's syndrome, relapsing polychondritis,systemic lupus erythematosus, discoid lupus erythematosus, systemicsclerosis, eosinophilic fasciitis, polymyositis, dermatomyositis,polymyalgia rheumatica, vasculitis, temporal arteritis, polyarteritisnodosa, Wegener's granulomatosis, mixed connective tissue disease, andjuvenile rheumatoid arthritis); gastrointestinal inflammatory diseasesor conditions [Crohn's disease, ulcerative colitis, irritable bowelsyndrome (spastic colon), fibrotic conditions of the liver, inflammationof the oral mucosa (stomatitis), and recurrent aphtous stomatitis];central nervous system inflammatory diseases or conditions (multiplesclerosis, Alzheimer's disease, and ischemia-reperfusion injury relatedto ischemic stroke); pulmonary inflammatory diseases or conditions(asthma, adult respiratory distress syndrome, and chronic obstructivepulmonary disease); (chronic) skin inflammatory diseases or conditions(psoriasis, allergic lesions, lichen planus, pityriasis rosea, contactdermatitis, atopic dermatitis, and pityriasis rubra pilaris); diseasesrelated to carbohydrate metabolism (diabetes mellitus and complicationsfrom diabetes mellitus) including microvascular and macrovasculardiseases (arterosclerosis, vascular retinopathies, retinopathy,nephropathy, nephrotic syndrome and neuropathy (polyneuropathy,mononeuropathies and autonomic neuropathy), foot ulcers, joint problems,and increased risk of infection); diseases related to aberrations inadipocyte differentiation or function or smooth muscle cell function(arterosclerosis and obesity); vascular diseases [atheromatousarterosclerosis, nonatheromatous arterosclerosis, ischemic heart diseaseincluding myocardial infarction and peripheral arterial occlusion,Raynaud's disease and phenomenon, and thromboangiitis obliterans(Buerger's disease)]; chronic arthritis; inflammatory bowel diseases;and skin dermatoses;

(4) diabetes mellitus;

(5) SSAO-mediated complications [diabetes mellitus (insulin dependentdiabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus(NIDDM)) and vascular complications (heart attack, angina, strokes,amputations, blindness, and renal insufficiency)], macular edema (forexample, diabetic and non-diabetic macular edema); and

(6) hepatitis and transplantation.

EMBODIMENTS FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

In the present specification, the “lower alkyl” refers to linear orbranched alkyl having 1 to 6 carbon atoms (which is hereinafter simplyreferred to as C₁₋₆), for example, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or thelike. In another embodiment, it is C₁₋₄ alkyl, and in still anotherembodiment, C₁₋₃ alkyl.

The “lower alkenyl” refers to linear or branched C₂₋₆ alkenyl, forexample, vinyl, propenyl, butenyl, pentenyl, 1-methylvinyl,1-methyl-2-propenyl, 1,3-butadienyl, 1,3-pentadienyl, or the like. Inanother embodiment, it is C₂₋₄ alkenyl, and in still another embodiment,C₂₋₃ alkenyl.

The “lower alkylene” refers to linear or branched C₁₋₆ alkylene, forexample, methylene, dimethylene, trimethylene, or the like. In anotherembodiment, it is C₁₋₄ alkylene, and in still another embodiment, C₁₋₃alkylene.

The “cycloalkyl” refers to a C₃₋₁₀ saturated hydrocarbon ring group,which may have a bridge. It is, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, or thelike. In another embodiment, it is C₃₋₈ cycloalkyl, and in still anotherembodiment, C₃₋₆ cycloalkyl.

The “cycloalkenyl” refers to a C₃₋₁₀ unsaturated hydrocarbon ring group,not including an aromatic hydrocarbon ring group. It is, for example,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl, or the like. In another embodiment, it is C₃₋₈cycloalkenyl, and in still another embodiment, C₃₋₆ cycloalkenyl.

The “aryl” refers to a C₆₋₁₄ monocyclic to tricyclic aromatichydrocarbon ring group, and includes a ring group fused with C₅₋₈cycloalkene at its double bond site. It is, for example, phenyl,naphthyl, 5-tetrahydronaphthyl, 4-indenyl, 1-fluorenyl, or the like. Inanother embodiment, it is phenyl.

The “hetero ring” means a ring group selected from i) a monocyclic 3- to8-membered, and in another embodiment, a 5- to 7-membered hetero ring,containing 1 to 4 hetero atoms selected from oxygen, sulfur, andnitrogen, and ii) a bi- to tricyclic hetero ring containing 1 to 5hetero atoms selected from oxygen, sulfur, and nitrogen, formed byring-fusion of said monocyclic hetero ring with one or two rings whichis selected from the group consisting of a monocyclic hetero ring, abenzene ring, C₅₋₈ cycloalkane, and C₅₋₈ cycloalkene. The ring atom,sulfur or nitrogen, may be oxidized to form an oxide or a dioxide.

Examples of the “hetero ring” group include the following embodiments:

(1) Monocyclic Saturated Hetero Ring Groups

(a) those containing 1 to 4 nitrogen atoms, for example, azepanyl,diazepanyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl,piperidyl, pyrazolidinyl, piperazinyl, azocanyl, hexamethyleneimino,homopiperazinyl, and the like;

(b) those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atomsand/or 1 to 2 oxygen atoms, for example, thiomorpholinyl, thiazolidinyl,isothiazolidinyl, oxazolidinyl, morpholinyl, oxazepanyl, and the like;

(c) those containing 1 to 2 sulfur atoms, for example,tetrahydrothiopyranyl and the like;

(d) those containing 1 to 2 sulfur atoms and 1 to 2 oxygen atoms, forexample, oxathiolanyl and the like;

(e) those containing 1 to 2 oxygen atoms, for example, oxiranyl,oxetanyl, dixolanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl,and the like;

(2) Monocyclic Unsaturated Hetero Ring Groups

(a) those containing 1 to 4 nitrogen atoms, for example, pyrrolyl,2-pyrrolinyl, imidazolyl, 2-imidazolinyl, pyrazolyl, 2-pyrazolinyl,pyridyl, dihydropyridyl, tetrahydropyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazolyl, tetrazolyl, triazinyl, dihydrotriazinyl,azepinyl, and the like;

(b) those containing 1 to 3 nitrogen atoms and 1 to 2 sulfur atomsand/or 1 to 2 oxygen atoms, for example, thiazolyl, isothiazolyl,thiadiazolyl, dihydrothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl,oxazinyl, and the like;

(c) those containing 1 to 2 sulfur atoms, for example, thienyl,thiepinyl, dihydrodithiopyranyl, dihydrodithionyl, 2H-thiopyranyl, andthe like;

(d) those containing 1 to 2 sulfur atoms and 1 to 2 oxygen atoms, forexample, dihydroxathiopyranyl and the like;

(e) those containing 1 to 2 oxygen atoms, for example, furyl,dihydrofuryl, pyranyl, 2H-pyranyl, oxepinyl, dioxolyl, and the like;

(3) Fused Polycyclic Saturated Hetero Ring Groups

(a) those containing 1 to 5 nitrogen atoms, for example, quinuclidinyl,7-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.2.2]nonanyl, and the like;

(b) those containing 1 to 4 nitrogen atoms and 1 to 3 sulfur atomsand/or 1 to 3 oxygen atoms, for example, trithiadiazaindenyl,dioxoloimidazolidinyl, and the like;

(c) those containing 1 to 3 sulfur atoms and/or 1 to 3 oxygen atoms, forexample, 2,6-dioxabicyclo[3.2.2]oct-7-yl and the like;

(4) Fused Polycyclic Unsaturated Hetero Ring Groups

(a) those containing 1 to 5 nitrogen atoms, for example, indolyl,isoindolyl, indolinyl, indolidinyl, benzoimidazolyl,dihydrobenzoimidazolyl, tetrahydrobenzoimidazolyl, quinolyl,tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl, indazolyl,imidazopyridyl, dihydroimidazopyridyl, benzotriazolyl,tetrazolopyridazinyl, carbazolyl, acridinyl, quinoxalinyl,dihydroquinoxalinyl, tetrahydroquinoxalinyl, phthalazinyl,dihydroindazolyl, benzopyrimidinyl, naphthyridinyl, quinazolinyl,cinnolinyl, pyridopyrrolidinyl, triazolopiperidinyl,9,10-dihydroacridine, and the like;

(b) those containing 1 to 4 nitrogen atoms and 1 to 3 sulfur atomsand/or 1 to 3 oxygen atoms, for example, benzothiazolyl,dihydrobenzothiazolyl, benzothiadiazolyl, imidazothiazolyl,imidazothiadiazolyl, benzoxazolyl, dihydrobenzoxazolyl,dihydrobenzoxadinyl, benzoxadiazolyl, benzoisothiazolyl,benzoisoxazolyl, thiazolopiperidinyl,5,6-dihydro-4H-pyrrolo[3,4-d][1,3]thiazol-2-yl, 10H-phenothiazine, andthe like;

(c) those containing 1 to 3 sulfur atoms, for example, benzothienyl,benzodithiopyranyl, chromanyl, dibenzo[b,d]thienyl, and the like;

(d) those containing 1 to 3 sulfur atoms and 1 to 3 oxygen atoms, forexample, benzoxathiopyranyl, phenoxazinyl, and the like;

(e) those containing 1 to 3 oxygen atoms, for example, benzodioxolyl,benzofuranyl, dihydrobenzofuranyl, isobenzofuranyl, chromanyl,chromenyl, isochromenyl, dibenzo[b,d]furanyl, methylenedioxyphenyl,ethylenedioxyphenyl, xanthenyl, and the like;

etc.

Further, the “hetero ring” group in (1) to (4) above is described as amonovalent group, but this may represent a divalent or higher group insome cases.

The “hetero ring” group includes a bicyclic hetero ring group having aspiro bond or a hetero ring group having a bridge structure, and it maybe, for example, a ring group as shown below.

The “monocyclic hetero ring” group refers to a hetero ring group havingone ring structure which is not fused with other rings as in (1) and(2), among the “hetero ring” groups above.

The “monocyclic saturated hetero ring” group refers to a hetero ringgroup which is saturated as in (1), among the “monocyclic hetero ring”groups above.

The “nitrogen-containing hetero ring” group refers to one containing atleast one nitrogen atom, as in (1)(a), (1)(b), (2)(a), (2)(b), (3)(a),(3)(b), (4)(a), (4)(b), and the like, among the “hetero rings” above.

The “nitrogen-containing monocyclic hetero ring” group refers to onecontaining at least one nitrogen atom, as in (1)(a), (1)(b), (2)(a),(2)(b), and the like, among the “monocyclic hetero ring” groups above.

The “nitrogen-containing monocyclic unsaturated hetero ring” grouprefers to an unsaturated hetero ring group, as in (2)(a), (2)(b), andthe like, among the “nitrogen-containing monocyclic hetero ring” groupsabove.

The “nitrogen-containing monocyclic saturated hetero ring” group refersto a saturated hetero ring group, as in (1)(a), (1)(b), and the like,among the “nitrogen-containing monocyclic hetero ring” groups above.

The “halogen” means F, Cl, Br, or I.

In the present specification, the expression “which may be substituted”represents non-substitution or substitution with 1 to 5 substituents”.Further, if it has a plurality of substituents, the substituents may bethe same as or different from one other.

Examples of the acceptable substituent used in the present specificationinclude the groups shown in (a) to (n) below, which may be chemicallyacceptable groups. Further, in another embodiment, the substituents maybe the groups shown in (a) to (m) below.

(a) halogen.

(b) OH, O-(lower alkyl) (in which the lower alkyl may be substitutedwith OH, COOH, COO-(lower alkyl), O-(lower alkyl), aryl, hetero ringgroup(s) (in which the hetero ring group may be substituted with OH,cycloalkyl, or lower alkyl which may be substituted with oxo (═O)), oroxo (═O)), O-(hetero ring group), or O-(aryl) (in which the aryl may besubstituted with O-(lower alkyl)); in another embodiment, OH, O-(loweralkyl) (in which the lower alkyl may be substituted with COOH,COO-(lower alkyl), O-(lower alkyl), or aryl), or O-(aryl) (in which thearyl may be substituted with O-(lower alkyl)); in still anotherembodiment, OH, O-(lower alkyl), or O-(aryl); and in further stillanother embodiment, OH, or O-(lower alkyl).

(c) amino which may be substituted with one or two lower alkyl group(s)(in which the lower alkyl may be substituted with one or more oxo (═O),OH, O-(lower alkyl), or aryl), SO₂-lower alkyl, cycloalkyl, aryl (inwhich the aryl may be substituted with COOH or COO-(lower alkyl)) orhetero ring group(s), or nitro; in another embodiment, amino which maybe substituted with one or two lower alkyl group(s) (in which the loweralkyl may be substituted with one or more oxo (═O), OH, O-(lower alkyl),or aryl), SO₂-lower alkyl, aryl (in which the aryl may be substitutedwith COOH) or hetero ring group(s), or nitro; in another embodiment,amino which may be substituted with one or two lower alkyl group(s),SO₂-lower alkyl, aryl or hetero ring group(s), or nitro.

(d) CHO, CO-(lower alkyl) (in which the lower alkyl may be substitutedwith OH, O-(lower alkyl), or oxo (═O)), CO-(cycloalkyl) (in which thecycloalkyl may be substituted with OH), CO-(aryl), CO-(hetero ringgroup) (in which the hetero ring group may be substituted with O-(loweralkyl)), or cyano; and in another embodiment, CHO, CO-(lower alkyl),CO-(cycloalkyl), CO-(aryl), CO-(hetero ring group), or cyano.

(e) aryl or cycloalkyl; further, this group may be substituted withhalogen, OH, COOH, COO-(lower alkyl which may be substituted with aryl),lower alkyl (in which the lower alkyl may be substituted with heteroring group(s) which may be substituted with oxo (═O), OH, O-(loweralkyl), COOH, COO-(lower alkyl), or oxo (═O)), O-(lower alkyl) (in whichthe lower alkyl may be substituted with hetero ring group(s)), aminowhich may be substituted with one or two lower alkyl group(s) (in whichthe lower alkyl may be substituted with one or more oxo (═O) group(s)),NHSO₂-(lower alkyl), or SO₂-(lower alkyl); and in another embodiment,the group may be substituted with COOH, lower alkyl (in which the loweralkyl may be substituted with hetero ring group(s) which may besubstituted with oxo (═O), OH or COOH), O-(lower alkyl) (in which thelower alkyl may be substituted with hetero ring group(s)), amino whichmay be substituted with one or two lower alkyl group(s) (in which thelower alkyl may be substituted with one or more oxo (═O) group(s)),NHSO₂-(lower alkyl), or SO₂-(lower alkyl).

(f) hetero ring group(s); and in another embodiment, monocyclic heteroring group(s); further, these hetero ring group and monocyclic heteroring group may be substituted with halogen, OH, oxo (═O), lower alkyl(in which the lower alkyl may be substituted with OH, O-(lower alkyl),or oxo (═O)), O-(lower alkyl which may be substituted with O-(loweralkyl) or oxo (═O)), aryl (in which the aryl may be substituted withhalogen or COOH), NHCO-(lower alkyl) or hetero ring group(s) (in whichthe hetero ring group may be substituted with COOH or O-(lower alkyl));and in another embodiment, the groups may be substituted with halogen,OH, oxo (═O), lower alkyl (in which the lower alkyl may be substitutedwith O-(lower alkyl) or oxo (═O)), O-(lower alkyl), aryl (in which thearyl may be substituted with halogen or COOH), NHCO-(lower alkyl) orhetero ring group(s) (in which the hetero ring group may be substitutedwith COOH, O-(lower alkyl)).

(g) COOH or COO-(lower alkyl); further, the lower alkyl in COO-(loweralkyl) may be substituted with aryl.

(h) CONH₂ or CONH(lower alkyl may be substituted with OH), CON(loweralkyl)₂; in another embodiment, CONH₂, CONH(lower alkyl), or CON(loweralkyl)₂.

(i) O—CO-(lower alkyl) or O—COO-(lower alkyl).

(j) oxo (═O).

(k) SO-(lower alkyl) (in which the lower alkyl may be substituted withO-(lower alkyl)), SO-(cycloalkyl), SO-(hetero ring group), SO-(aryl),SO₂-(lower alkyl) (in which the lower alkyl may be substituted withO-(lower alkyl)), SO₂-(cycloalkyl), SO₂-(hetero ring group), SO₂-(aryl),or sulfamoyl which may be substituted with one or two lower alkylgroup(s); in another embodiment, SO-(lower alkyl), SO-(cycloalkyl),SO-(hetero ring), SO-(aryl), SO₂-(lower alkyl), SO₂-(cycloalkyl),SO₂-(hetero ring group), SO₂-(aryl), or sulfamoyl which may besubstituted with one or two lower alkyl group(s).

(l) SO₂—NH₂, SO₂—NH(lower alkyl), or SO₂—N(lower alkyl)₂.

(m) lower alkyl group(s) which may each be substituted with one or moregroup(s) selected from the substituents shown in (a) to (k) above, orlower alkenyl group(s) which may each be substituted with one or moregroups selected from the substituents shown in (a) to (k) above; inanother embodiment, lower alkyl group(s) which may be substituted withone or more group(s) selected from the substituents shown in (a) to (k)above.

(n) lower alkyl group(s) which may each be substituted with one or moregroup(s) selected from the substituents shown in (a) to (l) above, orlower alkenyl group(s) which may each be substituted with one or moregroup(s) selected from the substituents shown in (a) to (l) above; inanother embodiment, lower alkyl group(s) which may be substituted withone or more group(s) selected from the substituents shown in (a) to (l)above.

Examples of the acceptable substituent of the “aryl which may besubstituted” and the “hetero ring group which may be substituted” in Ainclude the groups exemplified in (a) to (n) above, in anotherembodiment, the groups exemplified in (a) to (m) above, in still anotherembodiment, the groups exemplified in (b), (c), and (m) above, and infurther still another embodiment, the groups exemplified in (b) and (c)above.

Examples of the acceptable substituent of the “lower alkyl which may besubstituted” in R¹, R², R³, and R⁴ include the groups exemplified in (a)to (n) above, in another embodiment, the groups exemplified in (a) to(m) above, and in still another embodiment, the groups exemplified in(a) and (m) above.

Examples of the acceptable substituent of the “lower alkylene which maybe substituted” in E and J include the groups exemplified in (a) to (n)above, in another embodiment, the groups exemplified in (a) to (m)above, and in still another embodiment, the groups exemplified in (j)above.

Examples of the acceptable substituent of the “lower alkyl which may besubstituted” in G include the groups exemplified in (a) to (n) above,and in another embodiment, the groups exemplified in (a) to (m) above.

Examples of the acceptable substituent of the “lower alkyl which may besubstituted” in L include the groups exemplified in (a) to (n) above,and in another embodiment, the groups exemplified in (a) to (m) above.

Examples of the acceptable substituent of the “lower alkylene which maybe substituted” in U, V, and W include the groups exemplified in (a) to(n) above, in another embodiment, the groups exemplified in (a) to (m)above, and in still another embodiment, the groups exemplified in (j)above.

Examples of the acceptable substituent of the “lower alkyl which may besubstituted” in U and V include the groups exemplified in (a) to (n)above, in another embodiment, the groups exemplified in (a) to (m)above, and in still another embodiment, the groups exemplified in (b)and (c) above.

Examples of the acceptable substituent of the “lower alkyl which may besubstituted” in X include the groups exemplified in (a) to (n) above, inanother embodiment, the groups exemplified in (a) to (m) above, and instill another embodiment, the groups exemplified in (a) above.

Examples of the acceptable substituent of the “cycloalkyl which may besubstituted” in X include the groups exemplified in (a) to (n) above, inanother embodiment, the groups exemplified in (a) to (m) above, and instill another embodiment, the groups exemplified in (b) above.

Examples of the acceptable substituent of the “cycloalkenyl which may besubstituted” in X include the groups exemplified in (a) to (n) above, inanother embodiment, the groups exemplified in (a) to (m) above, and instill another embodiment, the groups exemplified in (b) above.

Examples of the acceptable substituent of the “aryl which may besubstituted” in X include the groups exemplified in (a) to (n) above, inanother embodiment, the groups exemplified in (a) to (m) above, and instill another embodiment, the groups exemplified in (b), (f), and (l)above.

Examples of the acceptable substituent of the “hetero ring group whichmay be substituted” in X include the groups exemplified in (a) to (n)above, and in another embodiment, the groups exemplified in (a) to (m)above.

Examples of the acceptable substituent of the “lower alkyl which may besubstituted” in R^(Q11), R^(Q12), R^(Q13), R^(Q21), R^(Q22), R^(Q23),R^(Q31), R^(Q41), R^(Q42), R^(Q43), R^(Q51), R^(Q52), R^(Q53), andR^(Q61) include the groups exemplified in (a) to (n) above, and inanother embodiment, the groups exemplified in (a) to (m) above.

Examples of the acceptable substituent of the “lower alkyl which may besubstituted” in R^(T11), R^(T12), R^(T13), R^(T21), R^(T22), R^(T23),R^(T31), R^(T41), R^(T42), R^(T43), R^(T51), R^(T52), R^(T53), R^(T61),R^(T62), and R^(T63) include the groups exemplified in (a) to (n) above,in another embodiment, the groups exemplified in (a) to (m) above, andin still another embodiment, the groups exemplified in (b), (c), (e),(f), (g), and (j) above.

Examples of the acceptable substituent of the “cycloalkyl which may besubstituted” in R^(T11), R^(T12), R^(T13), R^(T21), R^(T22), R^(T23),R^(T31), R^(T41), R^(T42), R^(T43), R^(T51), R^(T52), R^(T53), R^(T61),R^(T62), and R^(T63) include the groups exemplified in (a) to (n) above,in another embodiment, the groups exemplified in (a) to (m) above, andin still another embodiment, the groups exemplified in (m) above.

Examples of the acceptable substituent of the “aryl which may besubstituted” in R^(T11), R^(T12), R^(T13), R^(T21), R^(T22), R^(T23),R^(T31), R^(T41), R^(T42), R^(T43), R^(T51), R^(T52), R^(T53), R^(T61),R^(T62), and R^(T63) include the groups exemplified in (a) to (n) above,in another embodiment, the groups exemplified in (a) to (m) above, andin still another embodiment, the groups exemplified in (a), (g), and (m)above.

Examples of the acceptable substituent of the “hetero ring group whichmay be substituted” in R^(T11), R^(T12), R^(T13), R^(T21), R^(T22),R^(T23), R^(T31), R^(T41), R^(T42), R^(T43), R^(T51), R^(T52), R^(T53),R^(T61), R^(T62), and R^(T63) include the groups exemplified in (a) to(n) above, in another embodiment, the groups exemplified in (a) to (m)above, and in still another embodiment, the groups exemplified in (a),(b), (d), (g), and (m) above.

In another embodiment of the present invention, a compound representedby the formula (I′) or a salt thereof is provided.

(wherein

A is aryl which may be substituted or a hetero ring group which may besubstituted, R¹, R², R³, and R⁴ are the same as or different from eachother, and are H, halogen, or lower alkyl which may be substituted,

E is a single bond, or lower alkylene which may be substituted,

G is a single bond, O, NH, or N(lower alkyl which may be substituted),

J is a single bond, or lower alkylene which may be substituted,

L is O, NH, or N(lower alkyl which may be substituted),

U is a single bond, O, NH, N(lower alkyl which may be substituted), SO₂,or lower alkylene which may be substituted,

V is a single bond, O, NH, N(lower alkyl which may be substituted), orlower alkylene which may be substituted,

W is a single bond, SO₂, or lower alkylene which may be substituted, and

X is H, OH, NH₂, lower alkyl which may be substituted, O-(lower alkylwhich may be substituted), NH(lower alkyl which may be substituted),N(lower alkyl which may be substituted)₂, cycloalkyl which may besubstituted, O-(cycloalkyl which may be substituted), aryl which may besubstituted, O-(aryl which may be substituted), a hetero ring groupwhich may be substituted, or O-(hetero ring group which may besubstituted)).

Embodiments of the groups of the present invention are described below.

(1) A is

Q¹ is a single bond, CR^(Q11)R^(Q12), or NR^(Q13), Q² isCR^(Q21)R^(Q22), or NR^(Q23), Q³ is CR^(Q31) or N, Q⁴ is CR^(Q41)R^(Q42)or NR^(Q43), Q⁵ is a single bond, CR^(Q51)R^(Q52), or NR^(Q53), Q⁶ isCR^(Q61) or N, R^(Q11), R^(Q12), R^(Q13), R^(Q21), R^(Q22), R^(Q23),R^(Q31), R^(Q41), R^(Q42), R^(Q43), R^(Q51), R^(Q52), R^(Q53) andR^(Q61) are the same as or different from each other, and are H, loweralkyl which may be substituted, or O-(lower alkyl which may besubstituted), or R^(Q11) and R^(Q21), R^(Q11) and R^(Q23), R^(Q13) andR^(Q21), R^(Q13) and R^(Q23), R^(Q13) and R^(Q23), R^(Q31) and R^(Q41),R^(Q31) and R^(Q43), R^(Q51) and R^(Q61), or R^(Q53) and R^(Q61) may becombined with each other to form a new bond, or R^(Q11) and R^(Q61),R^(Q13) and R^(Q61), R^(Q21) and R^(Q31), R^(Q41) and R^(Q51), R^(Q43)and R^(Q51), R^(Q41) and R^(Q53), or R^(Q43) and R^(Q53) may be combinedwith each other to form a new bond, or R^(Q11) and R^(Q12), R^(Q21) andR^(Q22), R^(Q41) and R^(Q42), R^(Q51) and R^(Q52) may be combined witheach other to form oxo (═O).

(2) A is

Q¹ is CR^(Q12) or N, Q² is CR^(Q22) or N, Q⁴ is CR^(Q42) or N, Q⁵ isCR^(Q52) or N, and R^(Q12), R^(Q22), R^(Q42) and R^(Q52) are the same asor different from each other, and are H, lower alkyl which may besubstituted, or O-(lower alkyl which may be substituted).

(3) A is

Q¹ is a single bond or CR^(Q11)R^(Q12), Q³ is CR^(Q31) or N, Q⁵ is asingle bond or CR^(Q51)R^(Q52), Q⁶ is CR^(Q61) or N, in which either oneof Q³ and Q⁶ is N, R^(Q11), R^(Q12), R^(Q21), R^(Q22), R^(Q31), R^(Q41),R^(Q42), R^(Q51), R^(Q52) and R^(Q61) are the same as or different fromeach other, and are H, lower alkyl which may be substituted, or O-(loweralkyl which may be substituted), or R^(Q51) and R^(Q61) may be combinedwith each other to form a new bond, or R^(Q11) and R^(Q12), R^(Q21) andR^(Q22), R^(Q41) and R^(Q42), or R^(Q51) and R^(Q52) may be combinedwith each other to form oxo (═O).

(4) R^(Q12), R^(Q22), R^(Q42) and R^(Q52) are H.

(5) R^(Q11), R^(Q12), R^(Q21), R^(Q22), R^(Q31), R^(Q41), R^(Q42),R^(Q51), R^(Q52) and R^(Q61) are the same as or different from eachother, and are H, or R^(Q51) and R^(Q61) may be combined with each otherto form a new bond, or R^(Q11) and R^(Q12) may be combined with eachother to form oxo (═O); and in another embodiment, R^(Q11), R^(Q12),R^(Q21), R^(Q22), R^(Q31), R^(Q41), R^(Q42), R^(Q51), R^(Q52) andR^(Q61) are H.

(6) Q¹ is N, Q² is CR^(Q22), Q⁴ is CR^(Q42), and Q⁵ is N.

(7) Q¹ is CR^(Q12), Q² is CR^(Q22), Q⁴ is CR^(Q42), and Q⁵ is N.

(8) Q¹ is CR^(Q11), R^(Q12), Q³ is N, Q⁵ is CR^(Q51), R^(Q52), and Q⁶ isCR^(Q61) or N.

(9) Q¹ is CR^(Q11)R^(Q12), Q³ is N, Q⁵ is CR^(Q51)R^(Q52), and Q⁶ is N.

(10) Q¹ is CR^(Q11)R^(Q12), Q³ is N, Q⁵ is CR^(Q51)R^(Q52), and Q⁶ isCR^(Q61).

(11) Q¹ is CR^(Q11), R^(Q12), Q³ is CR^(Q31), Q⁵ is CR^(Q51)R^(Q52), andQ⁶ is N.

(12) Q¹ is a single bond, Q³ is N, Q⁵ is a single bond, and Q⁶ isCR^(Q61).

(13) R¹, R², R³ and R⁴ are the same as or different from each other, andare H or halogen; in another embodiment, R¹, R² and R³ are H, and R⁴ ishalogen; and in still another embodiment, R¹, R² and R³ are H, and R⁴ isF.

(14) E is a single bond.

(15) E is lower alkylene which may be substituted with oxo (═O).

(16) G is a single bond.

(17) G is O.

(18) G is NH.

(19) J is a single bond.

(20) J is lower alkylene which may be substituted.

(21) L is O.

(22) L is NH.

(23) U is a single bond.

(24) U is O.

(25) U is NH or N(lower alkyl which may be substituted).

(26) V is a single bond.

(27) V is lower alkylene which may be substituted with oxo (═O).

(28) W is a single bond.

(29) W is lower alkylene which may be substituted.

(30) X is H, OH, or NH₂.

(31) X is

T¹ is a single bond, CR^(T11)R^(T12), or NR^(T13), T² is CR^(T21)R^(T22)or NR^(T23), T³ is CR^(T31) or N, T⁴ is CR^(T41)R^(T42) or NR^(T43), T⁵is a single bond, (CR^(T11)R^(T52))_(m), or NR^(T53), T⁶ isCR^(T61)R^(T62) O, or NR^(T63), R^(T11), R^(T12), R^(T13), R^(T21),R^(T22), R^(T23), R^(T31), R^(T41), R^(T42), R^(T43), R^(T51), R^(T52),R^(T53), R^(T61) R^(T62) and R^(T63) are the same as or different fromeach other, and are H, OH, halogen, lower alkyl which may besubstituted, aryl which may be substituted, cycloalkyl which may besubstituted, a hetero ring group which may be substituted, O-(loweralkyl which may be substituted), NH(lower alkyl which may besubstituted), N(lower alkyl which may be substituted)₂, NH(aryl whichmay be substituted), N(aryl which may be substituted)₂, SO₂-(lower alkylwhich may be substituted), or SO₂-(cycloalkyl which may be substituted),or R^(T11) and R^(T61), R^(T11) and R^(T63), R^(T13) and R^(T61),R^(T13) and R^(T63), R^(T21) and R^(T31), R^(T23) and R^(T31), R^(T41)and R^(T51), R^(T43) and R^(T51), R^(T41) and R^(T53), or R^(T43) andR^(T53) may be combined with each other to form a new bond, or R^(T11)and R^(T12), R^(T21) and R^(T22), R^(T41) and R^(T42), R^(T51) andR^(T52), or R^(T61) and R^(T62) may be combined with each other to formoxo (═O), and m is 1 or 2.

(32) X is

T¹ is CR^(T12) or N, T² is CR^(T22) or N, T⁴ is CR^(T42) or N, T⁵ isCR^(T52) or N, T⁶ is CR^(T62) or N, R^(T12), R^(T22), R^(T42), R^(T52)and R^(T62) are the same as or different from each other, and are H, OH,halogen, lower alkyl which may be substituted, aryl which may besubstituted, cycloalkyl which may be substituted, a hetero ring groupwhich may be substituted, —O-(lower alkyl which may be substituted),NH-(lower alkyl which may be substituted), N(lower alkyl which may besubstituted)₂, NH-(aryl which may be substituted), N(aryl which may besubstituted)₂, SO₂-(lower alkyl which may be substituted), orSO₂-(cycloalkyl which may be substituted).

(33) R^(T11), R^(T12), R^(T21), R^(T22), R^(T31), R^(T41), R^(T42),R^(T51) and R^(T52) are the same as or different from each other, andare H, halogen, or lower alkyl which may be substituted; and in anotherembodiment, R^(T11), R^(T12), R^(T21), R^(T22), R^(T31), R^(T41),R^(T42), R^(T51) and R^(T52) are H; and in still another embodiment,R^(T11), R^(T12), R^(T21), R^(T22), R^(T31), R^(T41), R^(T42), R^(T51)and R^(T52) are the same as or different from each other, and are H orOH.

(34) R^(T13), R^(T23), R^(T43), R^(T53) are H.

(35) R^(T12), R^(T22), R^(T42) and R^(T52) are the same as or differentfrom each other, and are H, halogen, lower alkyl which may besubstituted, or O-(lower alkyl which may be substituted); in anotherembodiment, R^(T12), R^(T22), R^(T42) and R^(T52) are the same as ordifferent from each other, and are H, lower alkyl which may besubstituted with O-(lower alkyl), or O-(lower alkyl which may besubstituted with O-(lower alkyl)); in still another embodiment, R^(T12),R^(T22), R^(T42) and R^(T52) are the same as or different from eachother, and are H, methyl, methoxymethyl, or 2-methoxyethoxy; and infurther still another embodiment, R^(T12), R^(T22), R^(T42) and R^(T52)are H.

(36) R^(T62) is H.

(37) R^(T62) is halogen, OH, lower alkyl which may be substituted, orO-(lower alkyl which may be substituted).

(38) R^(T62) is OH, lower alkyl (in which the lower alkyl may besubstituted with O-(lower alkyl) or COOH), or O-(lower alkyl which maybe substituted with O-(lower alkyl)).

(39) R^(T63) is CO—(C₁₋₅alkyl which may be substituted), CO-(cycloalkylwhich may be substituted), CO-(aryl which may be substituted),CO-(nitrogen-containing monocyclic unsaturated hetero ring group whichmay be substituted), CON(lower alkyl which may be substituted)₂, orSO₂-(lower alkyl which may be substituted); in another embodiment,R^(T63) is CO—(C₁₋₅alkyl which may be substituted with O-(lower alkyl)or nitrogen-containing monocyclic unsaturated hetero ring(s)),CO-(cycloalkyl), CO-(aryl), CO-(nitrogen-containing monocyclicunsaturated hetero ring group), CON(lower alkyl)₂, or SO₂-(lower alkyl);in still another embodiment, R^(T63) is CO—(C₁₋₅alkyl which may besubstituted with O-(lower alkyl)), CO-(cycloalkyl), CO-(aryl),CO-(nitrogen-containing monocyclic unsaturated hetero ring group),CON(lower alkyl)₂, or SO₂-(lower alkyl); in further still anotherembodiment, R^(T63) is CO—(C₁₋₅ lower alkyl which may be substitutedwith O-(lower alkyl), CO-(cycloalkyl), or SO₂-(lower alkyl); in furtherstill another embodiment, R^(T63) is acetyl, propionyl, isobutyryl,pivaloyl, 2-ethoxy-1-oxoethyl, 2-methoxy-1-oxoethyl,3-methoxy-1-oxopropyl, 3-methoxy-2,2-dimethyl-1-oxopropyl,cyclopropylcarbonyl, benzoyl, pyridin-3-ylcarbonyl,dimethylaminocarbonyl, methylsulfonyl, or ethylsulfonyl; in furtherstill another embodiment, R^(T63) is acetyl, propionyl, isobutyryl,pivaloyl, 2-ethoxy-1-oxoethyl, 2-methoxy-1-oxoethyl,3-methoxy-1-oxopropyl, cyclopropylcarbonyl, benzoyl,pyridin-3-ylcarbonyl, dimethylaminocarbonyl, methylsulfonyl, orethylsulfonyl; and in further still another embodiment, R^(T63) isacetyl, propionyl, isobutyryl, pivaloyl, 2-ethoxy-1-oxoethyl,cyclopropylcarbonyl, benzoyl, pyridin-3-ylcarbonyl,dimethylaminocarbonyl, or methylsulfonyl.

(40) T¹ is a single bond, CR^(T11)R^(T12), or NR^(T13), T² is CR^(T2),R^(T22), T³ is CR^(T31) or N, T⁴ is CR^(T41)R^(T42), T⁵ is a singlebond, (CR^(T51)R^(T52))_(m), or NR^(T53), T⁶ is CR^(T61)R^(T62), O, orNR^(T63), R^(T21) and R^(T31) may be combined with each other to form anew bond, or R^(T11) and R^(T12) may be combined with each other to formoxo (═O).

(41) T¹ is a single bond or CRT R^(T12), T² is CR^(T21)R^(T22), T³ isCR^(T31) or N, T⁴ is CR^(T41)R^(T42), T⁵ is a single bond or(CR^(T51)R^(T52))_(m), and T⁶ is NR^(T63)

(42) T¹ is CR^(T11)R^(T12), T² is CR^(T21)R^(T22), T³ is CR^(T31), T⁴ isCR^(T41)R^(T42), T⁵ is (CR^(T51)R^(T52))_(m), and T⁶ is NR^(T63)

(43) T¹ is CR^(T11)R^(T12), T² is CR^(T21)R^(T22), T³ is CR^(T31), T⁴ isCR^(T41)R^(T42), T⁵ is (CR^(T51)R^(T52))_(m), and T⁶ is O.

(44) T¹ is a single bond, T² is CR^(T21)R^(T22), T³ is CR^(T31), T⁴ isCR^(T41)R^(T42), T⁵ is (CR^(T51)R^(T52))_(m), and T⁶ is O.

(45) T¹ is CR^(T11)R^(T12), T² is CR^(T21)R^(T22), T³ is N, T⁴ isCR^(T41)R^(T42), T⁵ is (CR^(T51)R^(T52))_(m), and T⁶ is O.

(46) T¹ is CR^(T11)R^(T12), T² is CR^(T21)R^(T22), T³ is N, T⁴ isCR^(T41)R^(T42), T⁵ is (CR^(T51)R^(T52))_(m), and T⁶ is CR^(T61)R^(T62)

(47) T¹ is a single bond, T² is CR^(T21)R^(T22), T³ is N, T⁴ isCR^(T41)R^(T42), T⁵ is a single bond, and T⁶ is CR^(T61)R^(T62).

(48) T¹ is a single bond, T² is CR^(T21)R^(T22), T³ is N, T⁴ isCR^(T41)R^(T42), T⁵ is (CR^(T51)R^(T52))_(m), and T⁶ is CR^(T61)R^(T62).

(49) T¹ is CR^(T11)R^(T12), T² is CR^(T21)R^(T22), T³ is N, T⁴ isCR^(T41)R^(T42), T⁵ is (CR^(T51)R^(T52))_(m), and T⁶ is NR^(T63).

(50) T¹ is CR^(T11)R^(T12), T² is CR^(T21)R^(T22), T³ is CR^(T3), T⁴ isCR^(T41)R^(T42), T⁵ is (CR^(T51)R^(T52))_(m), and T⁶ is CR^(T61)R^(T62).

(51) T¹ is N, T² is CR^(T22), T⁴ is CR^(T42), T⁵ is N, and T⁶ isCR^(T62).

(52) T¹ is CR^(T12), T² is CR^(T22), T⁴ is N, T⁵ is CR^(T52), and T⁶ isCR^(T62).

(53) T¹ is CR^(T2), T² is CR^(T22), T⁴ is CR^(T42), T⁵ is N, and T⁶ isCR^(T62).

(54) T¹ is CR^(T12), T² is CR^(T22) T⁴ is CR^(T42), T⁵ is CR^(T52), andT⁶ is N.

(55) m is 1.

(56) m is 2.

Other embodiments of the present invention are described below.

(57) A is

Q¹ is CR^(Q12) or N, Q² is CR^(Q22) or N, Q⁴ is CR^(Q42) or N, Q⁵ isCR^(Q52) or N, R^(Q12), R^(Q22), R^(Q42) and R^(Q52) are the same as ordifferent from each other, and are H, lower alkyl, O-(lower alkyl), orN(lower alkyl)₂, or

A is

Q¹ is a single bond or CR^(Q11)R^(Q12), Q³ is CR^(Q31) or N, Q⁵ is asingle bond or (CR^(Q51)R^(Q52))_(a), Q⁶ is CR^(Q61) or N, in whicheither one of Q³ and Q⁶ is N,

R^(Q11), R^(Q12), R^(Q21), R^(Q22), R^(Q31), R^(Q41), R^(Q42), R^(Q51),R^(Q52) and R^(Q61) are the same as or different from each other, andare H, OH, lower alkyl, or R^(Q51) and R^(Q61) may be combined with eachother to form a new bond, or R^(Q11) and R^(Q12) may be combined witheach other to form oxo (═O), and a is 1 or 2.

(58)

(58-1) A is

Q¹ is CR^(Q12) or N, Q² is CR^(Q22) or N, Q⁴ is CR^(Q42) or N, Q⁵ isCR^(Q52) or N, and R^(Q12), R^(Q22), R^(Q42) and R^(Q52) are the same asor different from each other, and are H, lower alkyl, O-(lower alkyl),or N(lower alkyl)₂.

(58-2) In (57) and (58-1), R^(Q12), R^(Q22), R^(Q42) and R^(Q52) are H.

(58-3) In (57) and (58-1) to (58-2), Q¹ is N, Q² is CR^(Q22), Q⁴ isCR^(Q42), and Q⁵ is N.

(58-4) In (57) and (58-1) to (58-2), Q¹ is CR^(Q12), Q² is CR^(Q22), Q⁴is CR^(Q42), and Q⁵ is N.

(59)

(59-1) A is

Q¹ is a single bond or CR^(Q11)R^(Q12), Q³ is CR^(Q31) or N, Q⁵ is asingle bond or (CR^(Q51)R^(Q52))_(a), Q⁶ is CR^(Q61) or N, in whicheither one of Q³ and Q⁶ is N,

R^(Q11), R^(Q12), R^(Q21), R^(Q22), R^(Q31), R^(Q41), R^(Q42), R^(Q51),R^(Q52) and R^(Q61) are the same as or different from each other, andare H, OH, or lower alkyl, or R^(Q51) and R^(Q61) may be combined witheach other to form a new bond, or R^(Q11) and R^(Q12) may be combinedwith each other to form oxo (═O), and a is 1 or 2.

(59-2) In (57) and (59-1), a is 1.

(59-3) In (57) and (59-1) to (59-2), R^(Q11), R^(Q12), R^(Q21), R^(Q22),R^(Q31), R^(Q41), R^(Q42), R^(Q51), R^(Q52) and R^(Q61) are the same asor different from each other, and are H, or R^(Q51) and R^(Q61) may becombined with each other to form a new bond, or R^(Q11) and R^(Q12) maybe combined with each other to form oxo (═O).

(59-4) In (57) and (59-1) to (59-3), Q¹ is CR^(Q11)R^(Q12), Q³ is N, Q⁵is CR^(Q51)R^(Q52), and Q⁶ is CR^(Q61), or N.

(59-5) In (57) and (59-1) to (59-3), Q¹ is CR^(Q11)R^(Q12), Q³ is N, Q⁵is CR^(Q51)R^(Q52), and Q⁶ is N.

(59-6) In (57) and (59-1) to (59-3), Q¹ is CR^(Q11)R^(Q12), Q³ is N, Q⁵is CR^(Q51), R^(Q52), and Q⁶ is CR^(Q61).

(59-7) In (57) and (59-1) to (59-3), Q¹ is CR^(Q11)R^(Q12), Q³ isCR^(Q31), Q⁵ is CR^(Q51)R^(Q52), and Q⁶ is N.

(59-8) In (57) and (59-1) to (59-3), Q¹ is a single bond, Q³ is N, Q⁵ isa single bond, and Q⁶ is CR^(Q61).

(60)

(60-1) X is

H,

OH,

NH₂,

lower alkyl which may be substituted with halogen,

O-(lower alkyl which may be substituted with OH),

NH(lower alkyl which may be substituted with oxo (═O)),

N(lower alkyl which may be substituted with O-(lower alkyl) or oxo(═O))₂,

NH—SO₂-(lower alkyl),

N(lower alkyl)-SO₂-(lower alkyl), cycloalkyl which may be substitutedwith group(s) selected from Group G^(XA1) below,

O-(cycloalkyl),

cycloalkenyl which may be substituted with group(s) selected from GroupG^(XA1) below,

aryl which may be substituted with group(s) selected from Group G^(XA1)below,

O-(aryl which may be substituted with O-(lower alkyl)), or

a hetero ring group which may be substituted with group(s) selected fromGroup G^(XA1) below, and

Group G^(XA1) is

i) halogen,

ii) OH,

iii) lower alkyl which may be substituted with group(s) selected fromthe group consisting of halogen; OH; O-(lower alkyl which may besubstituted with OH, aryl, O-(lower alkyl), or oxo (═O)); NH₂; NH(loweralkyl which may be substituted with OH); N(lower alkyl)₂;NH(cycloalkyl); NH(hetero ring group); cycloalkyl which may besubstituted with OH; aryl which may be substituted with O-(lower alkyl),COOH, or COO-(lower alkyl which may be substituted with aryl); heteroring group(s) which may be substituted with O-(lower alkyl), oxo (═O),NH(lower alkyl which may be substituted with oxo (═O)), or lower alkyl;and oxo (═O),

iv) O-(lower alkyl which may be substituted with OH, O-(lower alkyl),aryl, hetero ring group(s) (in which the hetero ring group may besubstituted with lower alkyl which may be substituted with cycloalkyl oroxo (═O)), or oxo (═O)),

v) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo(═O)),

vi) N(lower alkyl which may be substituted with oxo (═O))₂,

vii) NH-(aryl which may be substituted with COOH or COO-(lower alkyl)),

viii) cycloalkyl which may be substituted with group(s) selected fromthe group consisting of lower alkyl which may be substituted with OH;COOH; and COO-(lower alkyl),

ix) aryl which may be substituted with group(s) selected from the groupconsisting of halogen; lower alkyl (in which the lower alkyl may besubstituted with COOH or COO-(lower alkyl)); O-(lower alkyl); COOH; andCOO-(lower alkyl),

x) hetero ring group(s) which may be substituted with group(s) selectedfrom the group consisting of OH; halogen; lower alkyl which may besubstituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl whichmay be substituted with O-(lower alkyl)); and oxo (═O),

xi) O-(hetero ring group),

xii) SO₂-(lower alkyl which may be substituted with O-(lower alkyl)),

xiii) SO₂-(cycloalkyl),

xiv) SO₂-(aryl),

xv) NHSO₂-(lower alkyl), or

xvi) oxo (═O).

(60-2) X is

H,

OH,

NH₂,

lower alkyl which may be substituted with halogen,

O-(lower alkyl which may be substituted with OH),

NH(lower alkyl which may be substituted with oxo (═O)),

N(lower alkyl which may be substituted with O-(lower alkyl) or oxo(═O))₂,

NH—SO₂-(lower alkyl),

N(lower alkyl) —SO₂-(lower alkyl),

cycloalkyl which may be substituted with group(s) selected from GroupG^(XA2) below,

O-(cycloalkyl),

cycloalkenyl which may be substituted with group(s) selected from GroupG^(XA2) below,

aryl which may be substituted with group(s) selected from Group G^(XA2)below,

O-(aryl which may be substituted with O-(lower alkyl)), or

a hetero ring group which may be substituted with group(s) selected fromGroup G^(XA2) below,

G^(XA2) is

i) halogen,

ii) OH,

iii) lower alkyl which may be substituted with group(s) selected fromthe group consisting of halogen; OH; O-(lower alkyl which may besubstituted with OH, phenyl, O-(lower alkyl), or oxo (═O)); NH₂;NH(lower alkyl which may be substituted with OH); N(lower alkyl)₂;NH(cycloalkyl); NH(nitrogen-containing monocyclic hetero ring group);cycloalkyl which may be substituted with OH; phenyl which may besubstituted with O-(lower alkyl), COOH, or COO-(lower alkyl which may besubstituted with phenyl); monocyclic hetero ring group(s) which may besubstituted with O-(lower alkyl), oxo (═O), NH(lower alkyl which may besubstituted with oxo (═O)) or lower alkyl; and oxo (═O), iv) O-(loweralkyl which may be substituted with OH, O-(lower alkyl), phenyl,nitrogen-containing monocyclic hetero ring group(s) (in which thenitrogen-containing monocyclic hetero ring group may be substituted withlower alkyl which may be substituted with cycloalkyl or oxo (═O)), oroxo (═O)),

v) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo(═O)),

vi) N(lower alkyl which may be substituted with oxo (═O))₂,

vii) NH-(aryl which may be substituted with COOH or COO-(lower alkyl)),

viii) cycloalkyl which may be substituted with group(s) selected fromthe group consisting of lower alkyl which may be substituted with OH;COOH; and COO-(lower alkyl),

ix) aryl which may be substituted with group(s) selected from the groupconsisting of halogen; lower alkyl (in which the lower alkyl may besubstituted with COOH or COO-(lower alkyl)); O-(lower alkyl); COOH; andCOO-(lower alkyl),

x) hetero ring group(s) which may be substituted with group(s) selectedfrom the group consisting of OH; halogen; lower alkyl which may besubstituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl whichmay be substituted with O-(lower alkyl)); and oxo (═O),

xi) O-(monocyclic saturated hetero ring group),

xii) SO₂-(lower alkyl which may be substituted with O-(lower alkyl)),

xiii) SO₂-(cycloalkyl),

xiv) SO₂-(phenyl),

xv) NHSO₂-(lower alkyl), or

xvi) oxo (═O).

(60-3) X is

H,

OH,

NH₂,

lower alkyl which may be substituted with halogen,

O-(lower alkyl which may be substituted with OH),

NH(lower alkyl which may be substituted with oxo (═O)),

N(lower alkyl which may be substituted with O-(lower alkyl) or oxo(═O))₂,

NH—SO₂-(lower alkyl),

N(lower alkyl) —SO₂-(lower alkyl),

cycloalkyl which may be substituted with group(s) selected from GroupG^(XA3) below,

O-(cycloalkyl),

cycloalkenyl which may be substituted with group(s) selected from GroupG^(XA3) below,

phenyl which may be substituted with group(s) selected from GroupG^(XA3) below,

O-(phenyl which may be substituted with O-(lower alkyl)), or

a hetero ring group which may be substituted with group(s) selected fromGroup

G^(XA3) below, and

Group G^(XA3) is

i) halogen,

ii) OH,

iii) lower alkyl which may be substituted with group(s) selected fromthe group consisting of halogen; OH; O-(lower alkyl which may besubstituted with OH, phenyl, O-(lower alkyl), or oxo (═O)); NH₂;NH(lower alkyl which may be substituted with OH); N(lower alkyl)₂;NH(cycloalkyl); NH(thiazolyl); cycloalkyl which may be substituted withOH; phenyl which may be substituted with O-(lower alkyl), COOH, orCOO-(lower alkyl which may be substituted with phenyl);tetrahydropyranyl, furanyl, thiazolyl, morphonyl, azetidinyl,oxazolidinyl, or pyridyl, each of which may be substituted with O-(loweralkyl), oxo (═O), NH(lower alkyl which may be substituted with oxo (═O))or lower alkyl; and oxo (═O),

iv) O-(lower alkyl which may be substituted with OH, O-(lower alkyl),phenyl, piperidinyl or morphonyl (in which the piperidinyl or morphonylgroup may be substituted with lower alkyl which may be substituted withcycloalkyl or oxo (═O)), or oxo (═O)),

v) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo(═O)),

vi) N(lower alkyl which may be substituted with oxo (═O))₂,

vii) NH-(phenyl which may be substituted with COOH or COO-(loweralkyl)),

viii) cycloalkyl which may be substituted with group(s) selected fromthe group consisting of lower alkyl which may be substituted with OH;COOH; and COO-(lower alkyl),

ix) phenyl which may be substituted with group(s) selected from thegroup consisting of halogen; lower alkyl (in which the lower alkyl maybe substituted with COOH or COO-(lower alkyl)); O-(lower alkyl); COOH;and COO-(lower alkyl),

x) hetero ring group(s) which may be substituted with group(s) selectedfrom the group consisting of OH; halogen; lower alkyl which may besubstituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl whichmay be substituted with O-(lower alkyl)); and oxo (═O),

xi) O-(tetrahydropyranyl)

xii) SO₂-(lower alkyl which may be substituted with O-(lower alkyl)),

xiii) SO₂-(cycloalkyl),

xv) SO₂-(phenyl),

xv) NHSO₂-(lower alkyl), or

xvi) oxo (═O).

(60-4) X is

H,

OH,

NH₂,

lower alkyl which may be substituted with halogen,

O-(lower alkyl which may be substituted with OH),

NH(lower alkyl which may be substituted with oxo (═O)),

N(lower alkyl which may be substituted with O-(lower alkyl) or oxo(═O))₂,

NH—SO₂-(lower alkyl),

N(lower alkyl) —SO₂-(lower alkyl),

cycloalkyl which may be substituted with OH or O-(lower alkyl which maybe substituted with aryl or oxo (═O)),

O-(cycloalkyl),

cycloalkenyl which may be substituted with OH or O-(lower alkyl whichmay be substituted with aryl or oxo (═O)),

aryl which may be substituted with group(s) selected from the groupconsisting of lower alkyl which may be substituted with OH, O-(loweralkyl), hetero ring group(s) (in which the hetero ring group may besubstituted with oxo (═O)) or oxo (═O); O-(lower alkyl which may besubstituted with hetero ring group(s)); hetero ring group(s); NH(loweralkyl which may be substituted with oxo (═O)); N(lower alkyl which maybe substituted with oxo (═O))₂; NHSO₂-(lower alkyl); and SO₂-(loweralkyl),

O-(aryl which may be substituted with O-(lower alkyl)), or

a hetero ring group which may be substituted with group(s) selected fromGroup G^(XA4) below, and

Group G^(XA4) is

i) halogen,

ii) OH,

iii) lower alkyl which may be substituted with group(s) selected fromthe group consisting of halogen; OH; O-(lower alkyl which may besubstituted with OH, aryl, O-(lower alkyl), or oxo (═O)); NH₂; NH(loweralkyl which may be substituted with OH); N(lower alkyl)₂;NH(cycloalkyl); NH(hetero ring group); cycloalkyl which may besubstituted with OH; arly which may be substituted with O-(lower alkyl),COOH, or COO-(lower alkyl which may be substituted with aryl); heteroring group(s) which may be substituted with O-(lower alkyl), NH(loweralkyl which may be substituted with oxo (═O)), or lower alkyl; and oxo(═O),

iv) O-(lower alkyl which may be substituted with OH, O-(lower alkyl),aryl, hetero ring group(s) (in which the hetero ring group may besubstituted with lower alkyl which may be substituted with cycloalkyl oroxo (═O)), or oxo (═O)),

v) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo(═O)),

vi) NH-(aryl which may be substituted with COOH or COO-(lower alkyl)),

vii) cycloalkyl which may be substituted with group(s) selected from thegroup consisting of lower alkyl which may be substituted with OH; COOH;and COO-(lower alkyl),

viii) aryl which may be substituted with group(s) selected from thegroup consisting of halogen; lower alkyl (in which the lower alkyl maybe substituted with COOH or COO-(lower alkyl)); O-(lower alkyl); COOH;and COO-(lower alkyl),

ix) hetero ring group(s) which may be substituted with group(s) selectedfrom the group consisting of OH; halogen; lower alkyl which may besubstituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl whichmay be substituted with O-(lower alkyl)); and oxo (═O),

x) O-(hetero ring group),

xi) SO₂-(lower alkyl which may be substituted with O-(lower alkyl)),

xii) SO₂-(cycloalkyl),

xiii) SO₂-(aryl), or

xiv) oxo (═O).

(60-5) X is

H,

OH,

NH₂,

lower alkyl which may be substituted with halogen,

O-(lower alkyl which may be substituted with OH),

NH(lower alkyl which may be substituted with oxo (═O)),

N(lower alkyl which may be substituted with O-(lower alkyl) or oxo(═O))₂,

NH—SO₂-(lower alkyl),

N(lower alkyl) —SO₂-(lower alkyl),

cycloalkyl which may be substituted with OH or O-(lower alkyl which maybe substituted with phenyl or oxo (═O)),

O-(cycloalkyl),

cycloalkenyl which may be substituted with OH or O-(lower alkyl whichmay be substituted with phenyl or oxo (═O)),

aryl which may be substituted with group(s) selected from the groupconsisting of lower alkyl which may be substituted with OH, O-(loweralkyl), nitrogen-containing monocyclic hetero ring group(s) (in whichthe nitrogen-containing monocyclic hetero ring group may be substitutedwith oxo (═O)) or oxo (═O); O-(lower alkyl which may be substituted withnitrogen-containing monocyclic hetero ring group(s));nitrogen-containing monocyclic hetero ring group(s); NH(lower alkylwhich may be substituted with oxo (═O)); N(lower alkyl which may besubstituted with oxo (═O))₂; NHSO₂-(lower alkyl); and

SO₂-(lower alkyl),

O-(aryl which may be substituted with O-(lower alkyl)), or a hetero ringgroup which may be substituted with group(s) selected from Group G^(XA5)below, and

Group G^(XA5) is

i) halogen,

ii) OH,

iii) lower alkyl which may be substituted with group(s) selected fromthe group consisting of halogen; OH; O-(lower alkyl which may besubstituted with OH, phenyl, O-(lower alkyl), or oxo (═O)); NH₂;NH(lower alkyl which may be substituted with OH); N(lower alkyl)₂;NH(cycloalkyl); NH(nitrogen-containing monocyclic hetero ring group);cycloalkyl which may be substituted with OH; phenyl which may besubstituted with O-(lower alkyl), COOH, or COO-(lower alkyl which may besubstituted with phenyl); monocyclic hetero ring group(s) which may besubstituted with O-(lower alkyl), NH(lower alkyl which may besubstituted with oxo (═O)) or lower alkyl; and oxo (═O),

iv) O-(lower alkyl which may be substituted with OH, O-(lower alkyl),phenyl, nitrogen-containing monocyclic hetero ring group(s) (in whichthe nitrogen-containing monocyclic hetero ring group may be substitutedwith lower alkyl which may be substituted with cycloalkyl or oxo (═O)),or oxo (═O)),

v) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo(═O)),

vi) NH-(aryl which may be substituted with COOH or COO-(lower alkyl)),

vii) cycloalkyl which may be substituted with group(s) selected from thegroup consisting of lower alkyl which may be substituted with OH; COOH;and COO-(lower alkyl),

viii) aryl which may be substituted with group(s) selected from thegroup consisting of halogen; lower alkyl (in which the lower alkyl maybe substituted with COOH or COO-(lower alkyl)); O-(lower alkyl); COOH;and COO-(lower alkyl),

ix) hetero ring group(s) which may be substituted with group(s) selectedfrom the group consisting of OH; halogen; lower alkyl which may besubstituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl whichmay be substituted with O-(lower alkyl)); and oxo (═O),

x) O-(monocyclic saturated hetero ring group),

xi) SO₂-(lower alkyl which may be substituted with O-(lower alkyl)),

xii) SO₂-(cycloalkyl),

xiii) SO₂-(phenyl), or

xiv) oxo (═O).

(60-6) X is

H,

OH,

NH₂,

lower alkyl which may be substituted with halogen,

O-(lower alkyl which may be substituted with OH),

NH(lower alkyl which may be substituted with oxo (═O)),

N(lower alkyl which may be substituted with O-(lower alkyl) or oxo(═O))₂,

NH—SO₂-(lower alkyl),

N(lower alkyl) —SO₂-(lower alkyl),

cycloalkyl which may be substituted with OH or O-(lower alkyl which maybe substituted with phenyl or oxo (═O)),

O-(cycloalkyl),

cycloalkenyl which may be substituted with OH or O-(lower alkyl whichmay be substituted with phenyl or oxo (═O)),

phenyl which may be substituted with group(s) selected from the groupconsisting of lower alkyl which may be substituted with OH, O-(loweralkyl), oxazolidinyl (in which the oxazolidinyl group may be substitutedwith oxo (═O)) or oxo (═O); O-(lower alkyl which may be substituted withmorphonyl); pyridyl; morphonyl; NH(lower alkyl which may be substitutedwith oxo (═O)); N(lower alkyl which may be substituted with oxo (═O))₂;NHSO₂-(lower alkyl); and SO₂-(lower alkyl),

O-(phenyl which may be substituted with O-(lower alkyl)), or

a hetero ring group which may be substituted with group(s) selected fromGroup G^(XA6) below, and

Group G^(XA6) is

i) halogen,

ii) OH,

iii) lower alkyl which may be substituted with group(s) selected fromthe group consisting of halogen; OH; O-(lower alkyl which may besubstituted with OH, phenyl, O-(lower alkyl), or oxo (═O)); NH₂;NH(lower alkyl which may be substituted with OH); N(lower alkyl)₂;NH(cycloalkyl); NH(thiazolyl); cycloalkyl which may be substituted withOH; phenyl which may be substituted with O-(lower alkyl), COOH, orCOO-(lower alkyl which may be substituted with phenyl);tetrahydropyranyl, furanyl, thiazolyl, morphonyl, azetidinyl, orpyridyl, each of which may be substituted with O-(lower alkyl), NH(loweralkyl which may be substituted with oxo (═O)) or lower alkyl; and oxo(═O),

iv) O-(lower alkyl which may be substituted with OH, O-(lower alkyl),phenyl, piperidinyl or morphonyl (in which the piperidinyl or morphonylgroup may be substituted with lower alkyl which may be substituted withcycloalkyl or oxo (═O)), or oxo (═O)),

v) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo(═O)),

vi) NH-(phenyl which may be substituted with COOH or COO-(lower alkyl)),

vii) cycloalkyl which may be substituted with group(s) selected from thegroup consisting of lower alkyl which may be substituted with OH; COOH;and COO-(lower alkyl),

viii) phenyl which may be substituted with group(s) selected from thegroup consisting of halogen; lower alkyl (in which the lower alkyl maybe substituted with COOH or COO-(lower alkyl)); O-(lower alkyl); COOH;and COO-(lower alkyl),

ix) hetero ring group(s) which may be substituted with group(s) selectedfrom the group consisting of OH; halogen; lower alkyl which may besubstituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl whichmay be substituted with O-(lower alkyl)); and oxo (═O),

x) O-(tetrahydropyranyl)

xi) SO₂-(lower alkyl which may be substituted with O-(lower alkyl)),

xii) SO₂-(cycloalkyl),

xiii) SO₂-(phenyl), or

xiv) oxo (═O).

(61)

(61-1) X is H,

lower alkyl, O-(lower alkyl), O-(cycloalkyl),

cycloalkyl which may be substituted with group(s) selected from GroupG^(XB1) below,

cycloalkenyl which may be substituted with group(s) selected from GroupG^(XB1) below,

aryl which may be substituted with group(s) selected from Group G^(XB1)below, or

a hetero ring group which may be substituted with group(s) selected fromGroup G^(XB1) below, and

Group G^(XB1) is

i) OH,

ii) lower alkyl which may be substituted with group(s) selected from thegroup consisting of OH; O-(lower alkyl which may be substituted witharyl); NH(lower alkyl); N(lower alkyl)₂; NH(cycloalkyl); cycloalkylwhich may be substituted with OH; aryl; hetero ring group(s) which maybe substituted with lower alkyl; and oxo (═O),

iii) O-(lower alkyl which may be substituted with O-(lower alkyl), aryl,hetero ring group(s) (in which the hetero ring group may be substitutedwith lower alkyl which may be substituted with cycloalkyl or oxo (═O))or oxo (═O)),

iv) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo(═O)),

v) cycloalkyl which may be substituted with COOH or COO-(lower alkyl),

vi) hetero ring group(s) which may be substituted with group(s) selectedfrom the group consisting of OH; halogen; lower alkyl which may besubstituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl whichmay be substituted with O-(lower alkyl)); and oxo (═O),

vii) O-(hetero ring group),

viii) SO₂-(lower alkyl),

ix) SO₂-(cycloalkyl), or

x) oxo (═O).

(61-2) X is H,

lower alkyl, O-(lower alkyl), O-(cycloalkyl),

cycloalkyl which may be substituted with group(s) selected from GroupG^(XB2) below,

cycloalkenyl which may be substituted with group(s) selected from GroupG^(XB2) below,

aryl which may be substituted with group(s) selected from Group G^(XB2)below, or

a hetero ring group which may be substituted with group(s) selected fromGroup G^(XB2) below, and

Group G^(XB2) is

i) OH,

ii) lower alkyl which may be substituted with group(s) selected from thegroup consisting of OH; O-(lower alkyl which may be substituted withphenyl); NH(lower alkyl); N(lower alkyl)₂; NH(cycloalkyl); cycloalkylwhich may be substituted with OH; phenyl; monocyclic hetero ringgroup(s) which may be substituted with lower alkyl; and oxo (═O),

iii) O-(lower alkyl which may be substituted with O-(lower alkyl),phenyl, nitrogen-containing monocyclic saturated hetero ring group(s)(in which the nitrogen-containing monocyclic saturated hetero ring groupmay be substituted with lower alkyl which may be substituted withcycloalkyl or oxo (═O)) or oxo (═O)),

iv) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo(═O)),

v) cycloalkyl which may be substituted with COOH or COO-(lower alkyl),

vi) monocyclic hetero ring group(s) which may be substituted withgroup(s) selected from the group consisting of OH; halogen; lower alkylwhich may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(loweralkyl which may be substituted with O-(lower alkyl)); and oxo (═O),

vii) O-(monocyclic saturated hetero ring group),

viii) SO₂-(lower alkyl),

ix) SO₂-(cycloalkyl), or

x) oxo (═O).

(61-3) In (61-2), vi) is

vi) nitrogen-containing monocyclic hetero ring group(s) which may besubstituted with group(s) selected from the group consisting of OH;halogen; lower alkyl which may be substituted with OH, O-(lower alkyl),or oxo (═O); O-(lower alkyl which may be substituted with O-(loweralkyl)); and oxo (═O).

(61-4) X is H,

lower alkyl, O-(lower alkyl), O-(cycloalkyl),

cycloalkyl which may be substituted with group(s) selected from GroupG^(XB3) below,

cycloalkenyl which may be substituted with group(s) selected from GroupG^(XB3) below,

phenyl which may be substituted with group(s) selected from GroupG^(XB3) below, or

tetrahydropyranyl, tetrahydrofuranyl, 1,2-dihydropyridyl, thiazolyl,azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, imidazo[1,2-a]pyridyl, orbenzothiazolyl, which may substituted with group(s) selected from GroupG^(XB3) below, and

Group G^(XB3) is

i) OH,

ii) lower alkyl which may be substituted with group(s) selected from thegroup consisting of OH; O-(lower alkyl which may be substituted withphenyl); NH(lower alkyl); N(lower alkyl)₂; NH(cycloalkyl); cycloalkylwhich may be substituted with OH; phenyl; pyridyl which may besubstituted with lower alkyl; tetrahydropyranyl; and oxo (═O),

iii) O-(lower alkyl which may be substituted with O-(lower alkyl),phenyl, piperidinyl (in which piperidinyl group may be substituted withlower alkyl which may be substituted with cycloalkyl or oxo (═O)) or oxo(═O)),

iv) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo(═O)),

v) cycloalkyl which may be substituted with COOH or COO-(lower alkyl),

vi) 1,2-dihydropyridyl, pyridyl, azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, oxazepanyl, or tetrahydropyranyl, each ofwhich may be substituted with group(s) selected from the groupconsisting of OH; halogen; lower alkyl which may be substituted with OH,O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substitutedwith O-(lower alkyl)); and oxo (═O),

vii) O-(tetrahydropyranyl),

viii) SO₂-(lower alkyl),

ix) SO₂-(cycloalkyl), or

x) oxo (═O).

(61-5) X is H,

lower alkyl, O-(lower alkyl), O-(cycloalkyl),

cycloalkyl which may be substituted with group(s) selected from GroupG^(XB4) below,

cycloalkenyl which may be substituted with group(s) selected from GroupG^(XB4) below,

phenyl which may be substituted with group(s) selected from GroupG^(XB4) below, or

azetidinyl, pyrrolidinyl, piperidinyl, pyridyl, tetrahydrofuranyl,tetrahydropyranyl, or morpholinyl, each of which may be substituted withgroup(s) selected from Group G^(XB4) below, and

Group G^(XB4) is

i) OH,

ii) lower alkyl which may be substituted with group(s) selected from thegroup consisting of OH; O-(lower alkyl which may be substituted withphenyl); NH(lower alkyl); N(lower alkyl)₂; NH(cycloalkyl); cycloalkylwhich may be substituted with OH; phenyl; pyridyl which may besubstituted with lower alkyl; tetrahydropyranyl; and oxo (═O),

iii) O-(lower alkyl which may be substituted with O-(lower alkyl),phenyl, piperidinyl (in which the piperidinyl group may be substitutedwith lower alkyl which may be substituted with cycloalkyl or oxo (═O)),or oxo (═O)),

iv) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo(═O)),

v) cycloalkyl which may be substituted with COOH or COO-(lower alkyl),

vi) 1,2-dihydropyridyl, pyridyl, azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, or oxazepanyl, each of which may besubstituted with group(s) selected from the group consisting of OH;halogen; lower alkyl which may be substituted with OH, O-(lower alkyl),or oxo (═O); O-(lower alkyl which may be substituted with O-(loweralkyl)); and oxo (═O)

vii) O-(tetrahydropyranyl),

viii) SO₂-(lower alkyl),

ix) SO₂-(cycloalkyl), or

x) oxo (═O).

(61-6) X is H,

lower alkyl, O-(lower alkyl), O-(cycloalkyl),

cycloalkyl which may be substituted with group(s) selected from GroupG^(XB4) above,

cycloalkenyl which may be substituted with group(s) selected from GroupG^(XB4) above,

phenyl which may be substituted with group(s) selected from GroupG^(XB4) above, or

tetrahydropyranyl, tetrahydrofuranyl, 1,2-dihydropyridyl, thiazolyl,azetidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, imidazo[1,2-a]pyridyl, or benzothiazolyl, each of which maybe substituted with group(s) selected from Group G^(XB4) above.

(61-7) X is H,

lower alkyl, O-(lower alkyl), O-(cycloalkyl),

cycloalkyl which may be substituted with OH or O-(lower alkyl which maybe substituted with aryl or oxo (═O)),

cycloalkenyl which may be substituted with OH or O-(lower alkyl whichmay be substituted with aryl or oxo (═O)),

aryl which may be substituted with group(s) selected from the groupconsisting of lower alkyl which may be substituted with OH, O-(loweralkyl), or oxo (═O); O-(lower alkyl); and hetero ring group(s), or

a hetero ring group which may be substituted with group(s) selected fromGroup G^(XB5) below, and

Group G^(XB5) is

i) OH,

ii) lower alkyl which may be substituted with group(s) selected from thegroup consisting of OH; O-(lower alkyl which may be substituted witharyl); NH(lower alkyl); N(lower alkyl)₂; NH(cycloalkyl); cycloalkylwhich may be substituted with OH; aryl; hetero ring group(s) which maybe substituted with lower alkyl; and oxo (═O),

iii) O-(lower alkyl which may be substituted with O-(lower alkyl) orhetero ring group(s) (in which the hetero ring group may be substitutedwith lower alkyl which may be substituted with cycloalkyl or oxo (═O))),

iv) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo(═O)),

v) cycloalkyl which may be substituted with COOH or COO-(lower alkyl),

vi) hetero ring group(s) which may be substituted with group(s) selectedfrom the group consisting of OH; halogen; lower alkyl which may besubstituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl whichmay be substituted with O-(lower alkyl)); and oxo (═O),

vii) O-(hetero ring group),

viii) SO₂-(lower alkyl),

ix) SO₂-(cycloalkyl), or

x) oxo (═O).

(61-8) X is H,

lower alkyl, O-(lower alkyl), O-(cycloalkyl),

cycloalkyl which may be substituted with OH or O-(lower alkyl which maybe substituted with phenyl or oxo (═O)),

cycloalkenyl which may be substituted with OH or O-(lower alkyl whichmay be substituted with phenyl or oxo (═O)),

aryl which may be substituted with group(s) selected from the groupconsisting of lower alkyl which may be substituted with OH, O-(loweralkyl), or oxo (═O); O-(lower alkyl); and nitrogen-containing monocyclicunsaturated hetero ring group(s), or

a hetero ring group which may be substituted with group(s) selected fromGroup G^(XB6) below,

Group G^(XB6) is

i) OH,

ii) lower alkyl which may be substituted with group(s) selected from thegroup consisting of OH; O-(lower alkyl which may be substituted withphenyl); NH(lower alkyl); N(lower alkyl)₂; NH(cycloalkyl); cycloalkylwhich may be substituted with OH; phenyl; monocyclic hetero ringgroup(s) which may be substituted with lower alkyl; and oxo (═O),

iii) O-(lower alkyl which may be substituted with O-(lower alkyl) ornitrogen-containing monocyclic saturated hetero ring group(s) (in whichthe nitrogen-containing monocyclic saturated hetero ring group may besubstituted with lower alkyl which may be substituted with cycloalkyl oroxo (═O))),

iv) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo(═O)),

v) cycloalkyl which may be substituted with COOH or COO-(lower alkyl),

vi) monocyclic hetero ring group(s) which may be substituted withgroup(s) selected from the group consisting of OH; halogen; lower alkylwhich may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(loweralkyl which may be substituted with O-(lower alkyl)); and oxo (═O),

vii) O-(monocyclic saturated hetero ring group),

viii) SO₂-(lower alkyl),

ix) SO₂-(cycloalkyl), or

x) oxo (═O).

(61-9) In (61-8), vi) is

vi) nitrogen-containing monocyclic hetero ring group(s) which may besubstituted with group(s) selected from the group consisting of OH;halogen; lower alkyl which may be substituted with OH, O-(lower alkyl),or oxo (═O); O-(lower alkyl which may be substituted with O-(loweralkyl)); and oxo (═O).

(61-10) X is H,

lower alkyl, O-(lower alkyl), O-(cycloalkyl),

cycloalkyl which may be substituted with OH or O-(lower alkyl which maybe substituted with phenyl or oxo (═O)),

cycloalkenyl which may be substituted with OH or O-(lower alkyl whichmay be substituted with phenyl or oxo (═O)),

phenyl which may be substituted with group(s) selected from the groupconsisting of lower alkyl which may be substituted with OH, O-(loweralkyl), or oxo (═O); O-(lower alkyl); and pyridyl, or

tetrahydropyranyl, tetrahydrofuranyl, 1,2-dihydropyridyl, thiazolyl,azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, imidazo[1,2-a]pyridyl, orbenzothiazolyl, each of which may be substituted with group(s) selectedfrom Group G^(XB7) below, and

Group G^(XB7) is

i) OH,

ii) lower alkyl which may be substituted with group(s) selected from thegroup consisting of OH; O-(lower alkyl which may be substituted withphenyl); NH(lower alkyl); N(lower alkyl)₂; NH(cycloalkyl); cycloalkylwhich may be substituted with OH; phenyl; pyridyl which may besubstituted with lower alkyl; tetrahydropyranyl; and oxo (═O),

iii) O-(lower alkyl which may be substituted with O-(lower alkyl) orpiperidinyl (in which the piperidinyl group may be substituted withlower alkyl which may be substituted with cycloalkyl or oxo (═O))),

iv) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo(═O)),

v) cycloalkyl which may be substituted with COOH or COO-(lower alkyl),

vi) 1,2-dihydropyridyl, pyridyl, azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, oxazepanyl, or tetrahydropyranyl, each ofwhich may be substituted with group(s) selected from the groupconsisting of OH; halogen; lower alkyl which may be substituted with OH,O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substitutedwith O-(lower alkyl)); and oxo (═O),

vii) O-(tetrahydropyranyl),

viii) SO₂-(lower alkyl),

ix) SO₂-(cycloalkyl), or

x) oxo (═O).

(61-11) X is H,

lower alkyl, O-(lower alkyl), O-(cycloalkyl),

cycloalkyl which may be substituted with OH or O-(lower alkyl which maybe substituted with phenyl or oxo (═O)),

cycloalkenyl which may be substituted with OH or O-(lower alkyl whichmay be substituted with phenyl or oxo (═O)),

phenyl which may be substituted with group(s) selected from the groupconsisting of lower alkyl which may be substituted with OH, O-(loweralkyl), or oxo (═O); O-(lower alkyl); and pyridyl, or

azetidinyl, pyrrolidinyl, piperidinyl, pyridyl, tetrahydrofuranyl,tetrahydropyranyl, or morpholinyl, each of which may be substituted withgroup(s) selected from Group G^(XB8) below, and

Group G^(XB8) is

i) OH,

ii) lower alkyl which may be substituted with group(s) selected from thegroup consisting of OH; O-(lower alkyl which may be substituted withphenyl); NH(lower alkyl); N(lower alkyl)₂; NH(cycloalkyl); cycloalkylwhich may be substituted with OH; phenyl; pyridyl which may besubstituted with lower alkyl; tetrahydropyranyl; and oxo (═O),

iii) O-(lower alkyl which may be substituted with O-(lower alkyl) orpiperidinyl (in which the piperidinyl group may be substituted withlower alkyl which may be substituted with cycloalkyl or oxo (═O))),

iv) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo(═O)),

v) cycloalkyl which may be substituted with COOH or COO-(lower alkyl),

vi) 1,2-dihydropyridyl, pyridyl, azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, or oxazepanyl, each of which may besubstituted with group(s) selected from the group consisting of OH;halogen; lower alkyl which may be substituted with OH, O-(lower alkyl),or oxo (═O); O-(lower alkyl which may be substituted with O-(loweralkyl)); and oxo (═O)

vii) O-(tetrahydropyranyl),

viii) SO₂-(lower alkyl),

ix) SO₂-(cycloalkyl), or

x) oxo (═O).

(61-12) X is H,

lower alkyl, O-(lower alkyl), O-(cycloalkyl),

cycloalkyl which may be substituted with OH or O-(lower alkyl which maybe substituted with phenyl or oxo (═O)),

cycloalkenyl which may be substituted with OH or O-(lower alkyl whichmay be substituted with phenyl or oxo (═O)),

phenyl which may be substituted with group(s) selected from the groupconsisting of lower alkyl which may be substituted with OH, O-(loweralkyl), or oxo (═O); O-(lower alkyl); and pyridyl, or

tetrahydropyranyl, tetrahydrofuranyl, 1,2-dihydropyridyl, thiazolyl,azetidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, imidazo[1,2-a]pyridyl, or benzothiazolyl, each of which maybe substituted with group(s) selected from Group G^(XB8) above.

(62)

(62-1) X is OH, NH₂, lower alkyl which may be substituted with halogen,

O-(lower alkyl which may be substituted with OH), NH(lower alkyl whichmay be substituted with oxo (═O)), N(lower alkyl which may besubstituted with O-(lower alkyl) or oxo (═O))₂, NH—SO₂-(lower alkyl),N(lower alkyl)-SO₂-(lower alkyl), O-(cycloalkyl), or O-(aryl which maybe substituted with O-(lower alkyl)), or

X is

T¹ is a single bond, CR^(T11)R^(T12), O, or NR^(T13), T² isCR^(T21)R^(T22), or NR^(T23), T³ is CR^(T31) or N, T⁴ is CR^(T41)R^(T42)or O, T⁵ is a single bond, (CR^(T51)R^(T52))_(m), or NR^(T53), T⁶ isCR^(T61)R^(T62), O, S, SO₂, or NR^(T63),

R^(T11), R^(T12), R^(T21), R^(T22), R^(T31), R^(T41), R^(T42), R^(T51)and R^(T52) are the same as or different from each other, and are

H, OH, lower alkyl (in which the lower alkyl may be substituted with OH,NH₂, NH(lower alkyl which may be substituted with OH), O-(lower alkyl),or oxo (═O)), O-(lower alkyl), or nitrogen-containing monocyclicsaturated hetero ring group(s),

R^(T13), R^(T23) and R^(T53) are the same as or different from eachother, and are H or lower alkyl (in which the lower alkyl may besubstituted with O-(lower alkyl) or oxo (═O)),

R^(T61) is H, OH, or halogen,

R^(T62) is H, OH, halogen, lower alkyl (in which the lower alkyl may besubstituted with OH, halogen, O-(lower alkyl which may be substitutedwith OH, O-(lower alkyl), or oxo (═O)), NH₂, NH(lower alkyl which may besubstituted with OH), nitrogen-containing monocyclic saturated heteroring group(s) which may be substituted with O-(lower alkyl), or oxo(═O)), O-(lower alkyl which may be substituted with OH, O-(lower alkyl),aryl, or oxo (═O)), NH(lower alkyl which may be substituted with oxo(═O)), NH(aryl which may be substituted with COOH or COO-(lower alkyl)),SO₂-(lower alkyl), SO₂-(aryl), or a hetero ring group (in which thehetero ring group may be substituted with lower alkyl which may besubstituted with OH, O-(lower alkyl), or oxo (═O), or oxo (═O)),

R^(T63) is H,

lower alkyl which may be substituted with group(s) selected from thegroup consisting of OH; O-(lower alkyl); aryl (in which the aryl may besubstituted with O-(lower alkyl), COOH, or COO-(lower alkyl which may besubstituted with aryl)); NH₂; NH(lower alkyl); N(lower alkyl)₂;NH(cycloalkyl); cycloalkyl which may be substituted with OH; monocyclichetero ring group(s) which may be substituted with NH(lower alkyl whichmay be substituted with oxo (═O)); NH(nitrogen-containing monocyclicunsaturated hetero ring group); and oxo (═O),

a nitrogen-containing monocyclic unsaturated hetero ring group which maybe substituted with lower alkyl,

cycloalkyl which may be substituted with group(s) selected from thegroup consisting of lower alkyl which may be substituted with OH; COOH;and COO-(lower alkyl),

aryl which may be substituted with group(s) selected from the groupconsisting of halogen; lower alkyl (in which the lower alkyl may besubstituted with COOH or COO-(lower alkyl)); O-(lower alkyl); COOH; andCOO-(lower alkyl),

SO₂-(lower alkyl which may be substituted with O-(lower alkyl)), or

SO₂-(cycloalkyl), or

R^(T21) and R^(T31) may be combined with each other to form a new bond,or

R^(T1) and R^(T2), R^(T21) and R^(T22), R^(T41) and R^(T42), R^(T51) andR^(T52), or R^(T61) and R^(T62) may be combined with each other to formoxo (═O), and

m is 1 or 2, or

X is

T¹ is CR^(T12) or N, T² is CR^(T22) or N, T⁴ is CR^(T42) or N, T⁵ isCR^(T52) or N, T⁶ is CR^(T62) or N, and

R^(T12), R^(T22), R^(T42), R^(T52) and R^(T62) are the same as ordifferent from each other, and are H, lower alkyl which may besubstituted with OH or oxazolidinyl (in which the oxazolidinyl group maybe substituted with oxo (═O)), O-(lower alkyl which may be substitutedwith nitrogen-containing monocyclic saturated hetero ring group(s)),NH(lower alkyl which may be substituted with oxo (═O)), N(lower alkylwhich may be substituted with oxo (═O))₂, NH—SO₂-(lower alkyl),SO₂-(lower alkyl), or a nitrogen-containing monocyclic saturated heteroring group.

(62-2) X is OH, NH₂, lower alkyl which may be substituted with halogen,O-(lower alkyl which may be substituted with OH), NH(lower alkyl whichmay be substituted with oxo (═O)), N(lower alkyl which may besubstituted with O-(lower alkyl) or oxo (═O))₂, NH—SO₂-(lower alkyl),N(lower alkyl)-SO₂-(lower alkyl), O-(cycloalkyl), or O-(phenyl which maybe substituted with O-(lower alkyl)), or

X is

T¹ is a single bond, CR^(T11)R^(T12), O, or NR^(T13), T² isCR^(T21)R^(T22), O, or NR^(T23), T³ is CR^(T31) or N, T⁴ isCR^(T41)R^(T42) or O, T⁵ is a single bond, (CRTR^(T52))_(m), orNR^(T53), T⁶ is CR^(T61)R^(T62), O, S, SO₂, or NR^(T63),

R^(T11), R^(T12), R^(T21), R^(T22), R^(T31), R^(T41), R^(T42), R^(T51)and R^(T52) are the same as or different from each other, and are

H, OH, lower alkyl (in which the lower alkyl may be substituted with OH,NH₂, NH(lower alkyl which may be substituted with OH), O-(lower alkyl),or oxo (═O)), O-(lower alkyl), or morpholinyl,

R^(T13), R^(T23) and R^(T53) are the same as or different from eachother, and are H or lower alkyl (in which the lower alkyl may besubstituted with O-(lower alkyl) or oxo (═O)),

R^(T61) is H, OH, or halogen,

R^(T62) is H, OH, halogen, lower alkyl (in which the lower alkyl is OH,halogen, O-(lower alkyl which may be substituted with OH, O-(loweralkyl), or oxo (═O)), NH₂, NH(lower alkyl which may be substituted withOH), azetidinyl which may be substituted with O-(lower alkyl),morpholinyl, or oxo (═O)), O-(lower alkyl which may be substituted withOH, O-(lower alkyl), phenyl, or oxo (═O)), NH(lower alkyl which may besubstituted with oxo (═O)), NH(phenyl which may be substituted with COOHor COO-(lower alkyl)), SO₂-(lower alkyl), SO₂-(phenyl), ortetrahydropyranyl, piperidinyl, morpholinyl, pyridyl,dihydrobenzoimidazolinyl, or dihydroimidazopyridyl, each of which may besubstituted with lower alkyl (in which the lower alkyl may besubstituted with OH, O-(lower alkyl), or oxo (═O)) or oxo (═O),

R^(T63) is H,

lower alkyl which may be substituted with group(s) selected from thegroup consisting of OH; O-(lower alkyl); phenyl (in which the phenyl maybe substituted with O-(lower alkyl), COOH, or COO-(lower alkyl which maybe substituted with phenyl)); NH₂; NH(lower alkyl); N(lower alkyl)₂;NH(cycloalkyl); cycloalkyl which may be substituted with OH;tetrahydropyranyl, thiazolyl, pyridyl, or furanyl, each of which may besubstituted with NH(lower alkyl which may be substituted with oxo (═O));NH(thiazolyl); and oxo (═O),

pyridyl which may be substituted with lower alkyl,

cycloalkyl which may be substituted with group(s) selected from thegroup consisting of lower alkyl which may be substituted with OH; COOH;and COO-(lower alkyl),

phenyl which may be substituted with group(s) selected from the groupconsisting of halogen; lower alkyl (in which the lower alkyl may besubstituted with COOH or COO-(lower alkyl)); O-(lower alkyl); COOH; andCOO-(lower alkyl),

SO₂-(lower alkyl which may be substituted with O-(lower alkyl)), or

SO₂-(cycloalkyl), or

R^(T21) and R^(T31) may be combined with each other to form a new bond,or

R^(T11) and R^(T12), R^(T21) and R^(T22), R^(T41) and R^(T42), R^(T51)and R^(T52), or R^(T61) and R^(T62) may be combined with each other toform oxo (═O),

m is 1 or 2, or

X is

T¹ is CR^(T12) or N, T² is CR^(T22) or N, T⁴ is CR^(T42) or N, T⁵ isCR^(T52) or N, T⁶ is CR^(T62) or N, and

R^(T12), R^(T22), R^(T42), R^(T52) and R^(T62) are the same as ordifferent from each other, and are H, lower alkyl which may besubstituted with OH, or oxazolidinyl (in which the oxazolidinyl groupmay be substituted with oxo (═O)), O-(lower alkyl which may besubstituted with morpholinyl), NH(lower alkyl which may be substitutedwith oxo (═O)), N(lower alkyl which may be substituted with oxo (═O))₂,NH—SO₂-(lower alkyl), SO₂-(lower alkyl), or morpholinyl.

(63)

(63-1) X is lower alkyl, O-(lower alkyl), or O-(cycloalkyl), or

X is

T¹ is a single bond or CR^(T11)R^(T12), T² is CR^(T21)R^(T22), O, orNR^(T23), T³ is CR^(T31) or N, T⁴ is CR^(T41)R^(T42), T⁵ is a singlebond or (CR^(T51)R^(T52))_(m), T⁶ is CR^(T61)R^(T62), O, or NR^(T63)

R^(T11), R^(T12), R^(T21), R^(T22), R^(T31), R^(T41), R^(T42), R^(T51)and R^(T52) are the same as or different from each other, and are H, orOH,

R^(T23) is H, or CO—(C₁₋₅alkyl),

R^(T61) is H,

R^(T62) is H,

R^(T63) is cycloalkyl which may be substituted with COOH or COO-(loweralkyl), CO—(C₁₋₅alkyl which may be substituted with OH, oxo (═O),O-(lower alkyl) or nitrogen-containing monocyclic unsaturated heteroring(s)), CO-(cycloalkyl which may be substituted with OH), CO-(aryl),CO-(nitrogen-containing monocyclic unsaturated hetero ring group),CO—O—(C₁₋₅alkyl), CONH (lower alkyl), CON(lower alkyl)₂, CONH(cycloalkyl), SO₂-(lower alkyl), or SO₂-(cycloalkyl), and m is 1 or 2,or

X is

T¹ is CR^(T12) or N, T² is CR^(T22) or N, T⁴ is CR^(T42) or N, T⁵ isCR^(T52) or N, T⁶ is CR^(T62) or N, and

R^(T12), R^(T22), R^(T42), R^(T52) and R^(T62) are the same as ordifferent from each other, and are H, or O-(lower alkyl).

(63-2)

(63-2-1) In (63-1),

R^(T63) is CO—(C₁₋₅alkyl which may be substituted with O-(lower alkyl)or nitrogen-containing monocyclic unsaturated hetero ring(s)),CO-(cycloalkyl), CO-(aryl), CO-(nitrogen-containing monocyclicunsaturated hetero ring group), CON(lower alkyl)₂, or SO₂-(lower alkyl).

(63-2-2) In (63-1), R^(T63) is CO—(C₁₋₅alkyl which may be substitutedwith O-(lower alkyl)), CO-(cycloalkyl), CO-(aryl),CO-(nitrogen-containing monocyclic unsaturated hetero ring group),CON(lower alkyl)₂, or SO₂-(lower alkyl).

(63-2-3) In (63-1), R^(T63) is CO—(C₁₋₅ lower alkyl which may besubstituted with O-(lower alkyl)), CO-(cycloalkyl), or SO₂-(loweralkyl).

(63-2-4) In (63-1), R^(T63) is acetyl, propionyl, isobutyryl, pivaloyl,2-ethoxy-1-oxoethyl, 2-methoxy-1-oxoethyl, 3-methoxy-1-oxopropyl,3-methoxy-2,2-dimethyl-1-oxopropyl, cyclopropylcarbonyl, benzoyl,pyridin-3-ylcarbonyl, dimethylaminocarbonyl, methylsulfonyl, orethylsulfonyl.

(63-2-5) In (63-1), R^(T63) is acetyl, propionyl, isobutyryl, pivaloyl,2-ethoxy-1-oxoethyl, 2-methoxy-1-oxoethyl, 3-methoxy-1-oxopropyl,cyclopropylcarbonyl, benzoyl, pyridin-3-ylcarbonyl,dimethylaminocarbonyl, methylsulfonyl, or ethylsulfonyl.

(63-2-6) In (63-1), R^(T63) is acetyl, propionyl, isobutyryl, pivaloyl,2-ethoxy-1-oxoethyl, cyclopropylcarbonyl, benzoyl, pyridin-3-ylcarbonyl,dimethylaminocarbonyl, or methylsulfonyl.

(63-3)

(63-3-1) In (63-1) to (63-2), R^(T11), R^(T12), R^(T21), R^(T22),R^(T31), R^(T41), R^(T42), R^(T51) and R^(T52) are the same as ordifferent from each other, and are H or OH.

(63-3-2) In (63-1) to (63-2), R^(T11), R^(T12), R^(T21), R^(T22),R^(T31), R^(T41), R^(T42), R^(T51) and R^(T52) are H.

(63-4) In (63-1) to (63-3), R^(T23) is H.

(63-5) In (63-1) to (63-4), X is

T¹ is CR^(T12), T² is CH, T⁴ is CH, T⁵ is CR^(T52) or N, T⁶ is CH, and

R^(T12) and R^(T52) are the same as or different from each other, andare H or O-(lower alkyl).

(63-6)

(63-6-1) In (63-1) to (63-5), T¹ is a single bond or CR^(T11)R^(T2), T²is CR^(T21)R^(T22), T³ is CR^(T31) or N, T⁴ is CR^(T41)R^(T42), T⁵ is asingle bond or (CRTR^(T52))_(m), and T⁶ is NR^(T63).

(63-6-2) In (63-1) to (63-5), T¹ is CR^(T11)R^(T12), T² isCR^(T21)R^(T22), T³ is CR^(T31), T⁴ is CR^(T41)R^(T42), T⁵ is(CR^(T51)R^(T52))_(m), and T⁶ is NR^(T63)

(63-7) In (63-1) to (63-6), m is 1.

(64)

(64-1) X is H,

lower alkyl, O-(lower alkyl),

cycloalkyl which may be substituted with group(s) selected from GroupG^(XC1) below,

cycloalkenyl which may be substituted with group(s) selected from GroupG^(XC1) below,

aryl which may be substituted with group(s) selected from Group G^(XC1)below, or

a hetero ring group which may be substituted with group(s) selected fromGroup G^(XC1) below, and

Group G^(XC1) is

i) OH,

ii) lower alkyl which may be substituted with group(s) selected from thegroup consisting of OH; O-(lower alkyl which may be substituted witharyl); N(lower alkyl)₂; cycloalkyl; hetero ring group(s) which may besubstituted with lower alkyl; and oxo (═O),

iii) O-(lower alkyl which may be substituted with O-(lower alkyl), aryl,hetero ring group(s) (in which the hetero ring group may be substitutedwith lower alkyl which may be substituted with cycloalkyl or oxo (═O)),or oxo (═O)),

iv) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo(═O)),

v) cycloalkyl,

vi) hetero ring group(s) which may be substituted with group(s) selectedfrom the group consisting of OH; halogen; lower alkyl which may besubstituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl whichmay be substituted with O-(lower alkyl)); and oxo (═O),

vii) O-(hetero ring group),

viii) SO₂-(lower alkyl),

ix) SO₂-(cycloalkyl), or

x) oxo (═O).

(64-2) X is H,

lower alkyl, O-(lower alkyl),

cycloalkyl which may be substituted with group(s) selected from GroupG^(XC2) below,

cycloalkenyl which may be substituted with group(s) selected from GroupG^(XC2) below,

aryl which may be substituted with group(s) selected from Group G^(XC2)below, or

a hetero ring group which may be substituted with group(s) selected fromGroup G^(XC2) below, and

Group G^(XC2) is

i) OH,

ii) lower alkyl which may be substituted with group(s) selected from thegroup consisting of OH; O-(lower alkyl which may be substituted withphenyl); N(lower alkyl)₂; cycloalkyl; monocyclic hetero ring group(s)which may be substituted with lower alkyl; and oxo (═O),

iii) O-(lower alkyl which may be substituted with O-(lower alkyl),phenyl, nitrogen-containing monocyclic saturated hetero ring group(s)(in which the nitrogen-containing monocyclic saturated hetero ring groupmay be substituted with lower alkyl which may be substituted withcycloalkyl or oxo (═O)),

iv) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo(═O)),

v) cycloalkyl,

vi) monocyclic hetero ring group(s) which may be substituted withgroup(s) selected from the group consisting of OH; halogen; lower alkylwhich may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(loweralkyl which may be substituted with O-(lower alkyl)); and oxo (═O),

vii) O-(tetrahydropyranyl),

viii) SO₂-(lower alkyl),

ix) SO₂-(cycloalkyl), or

x) oxo (═O).

(64-3) In (64-2), vi) of Group G^(XC2) is

vi) nitrogen-containing monocyclic hetero ring group(s) which may besubstituted with group(s) selected from the group consisting of OH;halogen; lower alkyl which may be substituted with OH, O-(lower alkyl),or oxo (═O); O-(lower alkyl which may be substituted with O-(loweralkyl)); and oxo (═O).

(64-4) X is H,

lower alkyl, O-(lower alkyl), cycloalkyl which may be substituted withgroup(s) selected from Group G^(XC3) below,

cycloalkenyl which may be substituted with group(s) selected from GroupG^(XC3) below

phenyl which may be substituted with group(s) selected from GroupG^(XC3) below, or

tetrahydropyranyl, tetrahydrofuranyl, 1,2-dihydropyridyl, thiazolyl,piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,imidazo[1,2-a]pyridyl, or benzothiazolyl, each of which may besubstituted with group(s) selected from Group G^(XC3) below, and

G^(XC3) is

i) OH,

ii) lower alkyl which may be substituted with group(s) selected from thegroup consisting of OH; O-(lower alkyl which may be substituted withphenyl); N(lower alkyl)₂; cycloalkyl; pyridyl which may be substitutedwith lower alkyl; tetrahydropyranyl; and oxo (═O),

iii) O-(lower alkyl which may be substituted with O-(lower alkyl),phenyl, piperidinyl (in which the piperidinyl group may be substitutedwith lower alkyl which may be substituted with cycloalkyl or oxo (═O)),or oxo (═O)),

iv) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo(═O)),

v) cycloalkyl,

vi) 1,2-dihydropyridyl, pyridyl, azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, oxazepanyl, or tetrahydropyranyl, each ofwhich may be substituted with group(s) selected from the groupconsisting of OH; halogen; lower alkyl which may be substituted with OH,O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substitutedwith O-(lower alkyl)); and oxo (═O),

vii) O-(tetrahydropyranyl),

viii) SO₂-(lower alkyl),

ix) SO₂-(cycloalkyl), or

x) oxo (═O).

(64-5) X is H,

lower alkyl, O-(lower alkyl),

cycloalkyl which may be substituted with group(s) selected from GroupG^(XC4) below,

cycloalkenyl which may be substituted with group(s) selected from GroupG^(XC4) phenyl which may be substituted with group(s) selected fromGroup G^(XC4), or

tetrahydropyranyl, tetrahydrofuranyl, 1,2-dihydropyridyl, piperidinyl,pyridyl, pyrimidinyl, or imidazo[1,2-a]pyridyl, each of which may besubstituted with group(s) selected from Group G^(XC4), and

G^(XC4) is

i) OH,

ii) lower alkyl which may be substituted with group(s) selected from thegroup consisting of OH; O-(lower alkyl which may be substituted withphenyl); N(lower alkyl)₂; cycloalkyl; pyridyl which may be substitutedwith lower alkyl; tetrahydropyranyl; and oxo (═O),

iii) O-(lower alkyl which may be substituted with O-(lower alkyl),phenyl, piperidinyl (in which the piperidinyl group may be substitutedwith lower alkyl which may be substituted with cycloalkyl or oxo (═O)),or oxo (═O)),

iv) NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo(═O)),

v) cycloalkyl,

vi) 1,2-dihydropyridyl, pyridyl, azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, or oxazepanyl, each of which may besubstituted with group(s) selected from the group consisting of OH;halogen; lower alkyl which may be substituted with OH, O-(lower alkyl),or oxo (═O); O-(lower alkyl which may be substituted with O-(loweralkyl)); and oxo (═O),

vii) O-(tetrahydropyranyl),

viii) SO₂-(lower alkyl),

ix) SO₂-(cycloalkyl), or

x) oxo (═O).

(64-6) X is H,

lower alkyl, O-(lower alkyl),

cycloalkyl which may be substituted with OH or O-(lower alkyl which maybe substituted with aryl or oxo (═O)),

cycloalkenyl which may be substituted with OH or O-(lower alkyl whichmay be substituted with aryl or oxo (═O)),

aryl which may be substituted with group(s) selected from the groupconsisting of lower alkyl which may be substituted with OH, O-(loweralkyl), or oxo (═O); O-(lower alkyl); and hetero ring group(s), or

a hetero ring group which may be substituted with group(s) selected fromGroup G^(XC5) below, and

G^(XC5) is

i) lower alkyl which may be substituted with group(s) selected from thegroup consisting of OH; O-(lower alkyl which may be substituted witharyl); N(lower alkyl)₂; cycloalkyl; hetero ring group(s) which may besubstituted with lower alkyl; and oxo (═O),

ii) O-(lower alkyl which may be substituted with O-(lower alkyl) orhetero ring group(s) (in which the hetero ring group may be substitutedwith lower alkyl which may be substituted with cycloalkyl or oxo (═O))),

iii) NH-(lower alkyl which may be substituted with O-(lower alkyl) oroxo (═O)),

iv) cycloalkyl,

v) hetero ring group(s) which may be substituted with group(s) selectedfrom the group consisting of OH; halogen; lower alkyl which may besubstituted with OH, O-(lower alkyl), or oxo (═O); O-(lower alkyl whichmay be substituted with O-(lower alkyl)); and oxo (═O),

vi) O-(hetero ring group),

vii) SO₂-(lower alkyl),

viii) SO₂-(cycloalkyl), or

ix) oxo (═O).

(64-7) X is H,

lower alkyl, O-(lower alkyl),

cycloalkyl which may be substituted with OH or O-(lower alkyl which maybe substituted with phenyl or oxo (═O)),

cycloalkenyl which may be substituted with OH or O-(lower alkyl whichmay be substituted with phenyl or oxo (═O)),

aryl which may be substituted with group(s) selected from the groupconsisting of lower alkyl which may be substituted with OH, O-(loweralkyl), or oxo (═O); O-(lower alkyl); and nitrogen-containing monocyclicunsaturated hetero ring group(s), or

a hetero ring group which may be substituted with group(s) selected fromGroup G^(XC6) below, and

G^(XC6) is

i) lower alkyl which may be substituted with group(s) selected from thegroup consisting of OH; O-(lower alkyl which may be substituted withphenyl); N(lower alkyl)₂; cycloalkyl; monocyclic hetero ring group(s)which may be substituted with lower alkyl; and oxo (═O),

ii) O-(lower alkyl which may be substituted with O-(lower alkyl) ornitrogen-containing monocyclic saturated hetero ring group(s) (in whichthe nitrogen-containing monocyclic saturated hetero ring group may besubstituted with lower alkyl which may be substituted with cycloalkyl oroxo (═O))),

iii) NH-(lower alkyl which may be substituted with O-(lower alkyl) oroxo (═O)),

iv) cycloalkyl,

v) monocyclic hetero ring group(s) which may be substituted withgroup(s) selected from the group consisting of OH; halogen; lower alkylwhich may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(loweralkyl which may be substituted with O-(lower alkyl)); and oxo (═O),

vi) O-(tetrahydropyranyl),

vii) SO₂-(lower alkyl),

viii) SO₂-(cycloalkyl), or

ix) oxo (═O).

(64-8) In (64-7), v) of Group G^(XC6) is

v) nitrogen-containing monocyclic hetero ring group(s) which may besubstituted with group(s) selected from the group consisting of OH;halogen; lower alkyl which may be substituted with OH, O-(lower alkyl),or oxo (═O); O-(lower alkyl which may be substituted with O-(loweralkyl)); and oxo (═O).

(64-9) X is H,

lower alkyl, O-(lower alkyl),

cycloalkyl which may be substituted with OH or O-(lower alkyl which maybe substituted with phenyl or oxo (═O)),

cycloalkenyl which may be substituted with OH or O-(lower alkyl whichmay be substituted with phenyl or oxo (═O)),

phenyl which may be substituted with group(s) selected from the groupconsisting of lower alkyl which may be substituted with OH, O-(loweralkyl), or oxo (═O); O-(lower alkyl); and pyridyl, or

tetrahydropyranyl, tetrahydrofuranyl, 1,2-dihydropyridyl, thiazolyl,azetidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, imidazo[1,2-a]pyridyl, or benzothiazolyl, each of which maybe substituted with group(s) selected from Group G^(XC7) below, and

G^(XC7) is

i) lower alkyl which may be substituted with group(s) selected from thegroup consisting of OH; O-(lower alkyl which may be substituted withphenyl); N(lower alkyl)₂; cycloalkyl; pyridyl which may be substitutedwith lower alkyl; tetrahydropyranyl; and oxo (═O),

ii) O-(lower alkyl which may be substituted with O-(lower alkyl) orpiperidinyl (in which the piperidinyl group may be substituted withlower alkyl which may be substituted with cycloalkyl or oxo (═O))),

iii) NH-(lower alkyl which may be substituted with O-(lower alkyl) oroxo (═O)),

iv) cycloalkyl,

v) 1,2-dihydropyridyl, pyridyl, azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, oxazepanyl, or tetrahydropyranyl, each ofwhich may be substituted with group(s) selected from the groupconsisting of OH; halogen; lower alkyl which may be substituted with OH,O-(lower alkyl), or oxo (═O); O-(lower alkyl which may be substitutedwith O-(lower alkyl)); and oxo (═O),

vi) O-(tetrahydropyranyl),

vii) SO₂-(lower alkyl), viii) SO₂-(cycloalkyl), or

ix) oxo (═O).

(64-10) X is H,

lower alkyl, O-(lower alkyl),

cycloalkyl which may be substituted with OH or O-(lower alkyl which maybe substituted with phenyl or oxo (═O)),

cycloalkenyl which may be substituted with OH or O-(lower alkyl whichmay be substituted with phenyl or oxo (═O)),

phenyl which may be substituted with group(s) selected from the groupconsisting of lower alkyl which may be substituted with OH, O-(loweralkyl), or oxo (═O); O-(lower alkyl); and pyridyl, or

tetrahydropyranyl, tetrahydrofuranyl, 1,2-dihydropyridyl, azetidinyl,piperidinyl, pyridyl, pyrimidinyl, or imidazo[1,2-a]pyridyl, each ofwhich may be substituted with group(s) selected from Group G^(XC8)below, and

G^(XC8) is

i) lower alkyl which may be substituted with group(s) selected from thegroup consisting of OH; O-(lower alkyl which may be substituted withphenyl); N(lower alkyl)₂; cycloalkyl; pyridyl which may be substitutedwith lower alkyl; tetrahydropyranyl; and oxo (═O),

ii) O-(lower alkyl which may be substituted with O-(lower alkyl) orpiperidinyl (in which the piperidinyl group may be substituted withlower alkyl which may be substituted with cycloalkyl or oxo (═O))),

iii) NH-(lower alkyl which may be substituted with O-(lower alkyl) oroxo (═O)),

iv) cycloalkyl,

v) 1,2-dihydropyridyl, pyridyl, azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, or oxazepanyl, each of which may besubstituted with group(s) selected from the group consisting of OH;halogen; lower alkyl which may be substituted with OH, O-(lower alkyl),or oxo (═O); O-(lower alkyl which may be substituted with O-(loweralkyl)); and oxo (═O),

vi) O-(tetrahydropyranyl),

vii) SO₂-(lower alkyl),

viii) SO₂-(cycloalkyl), or

ix) oxo (═O).

(65)

(65-1) X is

H, lower alkyl, or O-(lower alkyl), or

X is

T¹ is a single bond, CR^(T11)R^(T12), or NR^(T13), T³ is CR^(T31) or N,T⁵ is a single bond or CR^(T51)R^(T52), T⁶ is a single bond,CR^(T61)R^(T62), O, or NR^(T63),

R^(T11), R^(T12), R^(T13), R^(T21), R^(T22), R^(T31), R^(T41), R^(T42),R^(T51), R^(T52), R^(T61), R^(T62) and R^(T63) are the same as ordifferent from each other, and are

H,

OH,

lower alkyl which may be substituted with group(s) selected from thegroup consisting of O-(lower alkyl which may be substituted with aryl);N(lower alkyl)₂; cycloalkyl; hetero ring group(s) which may besubstituted with lower alkyl; and oxo (═O),

O-(lower alkyl which may be substituted with aryl or oxo (═O)),

a hetero ring group which may be substituted with group(s) selected fromthe group consisting of lower alkyl which may be substituted with OH oroxo (═O); and oxo (═O),

SO₂-(lower alkyl), or

SO₂-(cycloalkyl), or

R^(T21) and R^(T31), or R^(T41) and R^(T51) may be combined with eachother to form a new bond, or

R^(T61) and R^(T62) may be combined with each other to form oxo (═O), or

X is

T¹ is CR^(T12) or N, T² is CR^(T22) or N, T⁴ is CR^(T42) or N, T⁵ isCR^(T52) or N, T⁶ is CR^(T62) or N,

R^(T12), R^(T22), R^(T42), R^(T52) and R^(T62) are the same as ordifferent from each other, and are

H,

lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo(═O), O-(lower alkyl which may be substituted with O-(lower alkyl) orhetero ring group(s) (in which the hetero ring group may be substitutedwith lower alkyl which may be substituted with cycloalkyl or oxo (═O))),

NH-(lower alkyl which may be substituted with O-(lower alkyl)),

cycloalkyl,

a hetero ring group which may be substituted with group(s) selected fromthe group consisting of OH; halogen; lower alkyl which may besubstituted with O-(lower alkyl) or oxo (═O); and O-(lower alkyl whichmay be substituted with O-(lower alkyl)), or

O-(hetero ring group), or

X is thiazolyl which may be substituted with morpholinyl or NH(loweralkyl which may be substituted with oxo (═O)), benzothiazolyl, orimidazo[1,2-a]pyridyl which may be substituted with lower alkyl.

(65-2) X is

H, lower alkyl, or O-(lower alkyl), or

X is

T¹ is a single bond, CR^(T11)R^(T12), or NR^(T13), T³ is CR^(T3) or N,T⁵ is a single bond or CR^(T51)R^(T52), T⁶ is a single bond,CR^(T61)R^(T62), O, or NR^(T63), R^(T11), R^(T12), R^(T13), R^(T21),R^(T22), R^(T31), R^(T41), R^(T42), R^(T51), R^(T52), R^(T61), R^(T62)and R^(T63) are the same as or different from each other, and are

H,

OH,

lower alkyl which may be substituted with group(s) selected from thegroup consisting of O-(lower alkyl which may be substituted withphenyl); N(lower alkyl)₂; cycloalkyl; monocyclic hetero ring group(s)which may be substituted with lower alkyl; and oxo (═O),

O-(lower alkyl which may be substituted with phenyl or oxo (═O)), amonocyclic hetero ring group which may be substituted with group(s)selected from the group consisting of lower alkyl which may besubstituted with OH or oxo (═O); and oxo (═O),

SO₂-(lower alkyl), or

SO₂-(cycloalkyl), or

R^(T21) and R^(T31), or R^(T41) and R^(T51) may be combined with eachother to form a new bond, or

R^(T61) and R^(T62) may be combined with each other to form oxo (═O), or

X is

T¹ is CR^(T12) or N, T² is CR^(T22) or N, T⁴ is CR^(T42) or N, T⁵ isCR^(T52) or N, T⁶ is CR^(T62) or N,

R^(T12), R^(T22), R^(T42), R^(T52) and R^(T62) are the same as ordifferent from each other, and are

H,

lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo(═O),

O-(lower alkyl which may be substituted with O-(lower alkyl) ornitrogen-containing monocyclic saturated hetero ring group(s) (in whichthe nitrogen-containing monocyclic saturated hetero ring group may besubstituted with lower alkyl which may be substituted with cycloalkyl oroxo (═O))),

NH-(lower alkyl which may be substituted with O-(lower alkyl)),

cycloalkyl,

a monocyclic hetero ring group which may be substituted with group(s)selected from the group consisting of OH; halogen; lower alkyl which maybe substituted with O-(lower alkyl) or oxo (═O); and O-(lower alkylwhich may be substituted with O-(lower alkyl)), or

O-(monocyclic hetero ring group), or

X is thiazolyl which may be substituted with morpholinyl or NH(loweralkyl which may be substituted with oxo (═O)), benzothiazolyl, orimidazo[1,2-a]pyridyl which may be substituted with lower alkyl.

(65-3) X is

H, lower alkyl, or O-(lower alkyl), or

X is

T¹ is a single bond, CR^(T11)R^(T12), or NR^(T13), T³ is CR^(T31) or N,T⁵ is a single bond or CR^(T51)R^(T52), T⁶ is a single bond,CR^(T61)R^(T62), O, or NR^(T63),

R^(T11), R^(T12), R^(T13), R^(T21), R^(T22), R^(T31), R^(T41), R^(T42),R^(T51), R^(T52), R^(T61), R^(T62) and R^(T63) are the same as ordifferent from each other, and are

H,

OH,

lower alkyl which may be substituted with group(s) selected from thegroup consisting of O-(lower alkyl which may be substituted withphenyl); N(lower alkyl)₂; cycloalkyl; monocyclic hetero ring group(s)which may be substituted with lower alkyl; and oxo (═O),

O-(lower alkyl which may be substituted with phenyl or oxo (═O)),

a nitrogen-containing monocyclic hetero ring group which may besubstituted with group(s) selected from the group consisting of loweralkyl which may be substituted with OH or oxo (═O); and oxo (═O),

SO₂-(lower alkyl), or

SO₂-(cycloalkyl), or

R^(T21) and R^(T31), or R^(T41) and R^(T51) may be combined with eachother to form a new bond, or

R^(T61) and R^(T62) may be combined with each other to form oxo (═O), or

X is

T¹ is CR^(T12) or N, T² is CR^(T22) or N, T⁴ is CR^(T42) or N, T⁵ isCR^(T52) or N, T⁶ is CR^(T62) or N,

R^(T12), R^(T22), R^(T42), R^(T52) and R^(T62) are the same as ordifferent from each other, and are

H,

lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo(═O),

O-(lower alkyl which may be substituted with O-(lower alkyl) ornitrogen-containing monocyclic saturated hetero ring group(s) (in whichthe nitrogen-containing monocyclic saturated hetero ring group may besubstituted with lower alkyl which may be substituted with cycloalkyl oroxo (═O))),

NH-(lower alkyl which may be substituted with O-(lower alkyl)),

cycloalkyl,

a nitrogen-containing monocyclic hetero ring group which may besubstituted with group(s) selected from the group consisting of OH;halogen; lower alkyl which may be substituted with O-(lower alkyl) oroxo (═O); and O-(lower alkyl which may be substituted with O-(loweralkyl)), or

O-(monocyclic saturated hetero ring group), or

X is thiazolyl which may be substituted with morpholinyl or NH(loweralkyl which may be substituted with oxo (═O)), benzothiazolyl, orimidazo[1,2-a]pyridyl which may be substituted with lower alkyl.

(65-4) X is

H,

lower alkyl, or

O-(lower alkyl), or

X is

T¹ is a single bond, CR^(T11)R^(T12), or NR^(T13), T³ is CR^(T31) or N,T⁵ is a single bond or CR^(T51)R^(T52), T⁶ is a single bond,CR^(T61)R^(T62), or NR^(T63),

R^(T11), R^(T12), R^(T31), R^(T21), R^(T22), R^(T31), R^(T41), R^(T42),R^(T51), R^(T52), R^(T61), R^(T62) and R^(T63) are the same as ordifferent from each other, and are

H,

OH,

lower alkyl which may be substituted with group(s) selected from thegroup consisting of O-(lower alkyl which may be substituted withphenyl); N(lower alkyl)₂; cycloalkyl; pyridyl which may be substitutedwith lower alkyl; tetrahydropyranyl; and oxo (═O),

O-(lower alkyl which may be substituted with phenyl or oxo (═O)),

1,2-dihydropyridyl, pyridyl, or tetrahydropyranyl, each of which may besubstituted with group(s) selected from the group consisting of loweralkyl which may be substituted with OH or oxo (═O); and oxo (═O),

SO₂-(lower alkyl), or

SO₂-(cycloalkyl), or

R^(T21) and R^(T31), or R^(T41) and R^(T51) may be combined with eachother to form a new bond, or

R^(T61) and R^(T62) may be combined with each other to form oxo (═O),

or,

X is

T¹ is CR^(T12) or N, T² is CR^(T22) or N, T⁴ is CR^(T42) or N, T⁵ isCR^(T52) or N, T⁶ is CR^(T62) or N,

R^(T12), R^(T22), R^(T42), R^(T52) and R^(T62) are the same as ordifferent from each other, and are

H,

lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo(═O),

O-(lower alkyl which may be substituted with O-(lower alkyl) orpiperidinyl (in which the piperidinyl group may be substituted withlower alkyl which may be substituted with cycloalkyl or oxo (═O))),

NH-(lower alkyl which may be substituted with O-(lower alkyl)),

cycloalkyl,

pyridyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, or oxazepanyl, each of which may be substituted withgroup(s) selected from the group consisting of OH; halogen; lower alkylwhich may be substituted with O-(lower alkyl) or oxo (═O); and O-(loweralkyl which may be substituted with O-(lower alkyl)), or

O-(tetrahydropyranyl), or

X is thiazolyl which may be substituted with morpholinyl or NH(loweralkyl which may be substituted with oxo (═O)), benzothiazolyl, orimidazo[1,2-a]pyridyl which may be substituted with lower alkyl.

(65-5) X is

H,

lower alkyl, or

O-(lower alkyl), or

X is

T¹ is a single bond, CR^(T11)R^(T12), or NR^(T13), T³ is CR^(T31) or N,T⁵ is a single bond or CR^(T51)R^(T52), T⁶ is a single bond,CR^(T61)R^(T62), O, or NR^(T63),

R^(T11), R^(T12), R^(T13), R^(T21), R^(T22), R^(T31), R^(T41), R^(T42),R^(T51), R^(T52), R^(T61), R^(T62) and R^(T63) are the same as ordifferent from each other, and are

H,

OH,

lower alkyl which may be substituted with group(s) selected from thegroup consisting of O-(lower alkyl which may be substituted withphenyl); N(lower alkyl)₂; cycloalkyl; pyridyl which may be substitutedwith lower alkyl; tetrahydropyranyl; and oxo (═O),

O-(lower alkyl which may be substituted with phenyl or oxo (═O)),

1,2-dihydropyridyl or pyridyl, each of which may be substituted withgroup(s) selected from the group consisting of lower alkyl which may besubstituted with OH or oxo (═O); and oxo (═O),

SO₂-(lower alkyl), or

SO₂-(cycloalkyl), or

R^(T21) and R^(T31), or R^(T41) and R^(T51) may be combined with eachother to form a new bond, or R^(T61) and R^(T62) may be combined witheach other to form oxo (═O), or

X is

T¹ is CR^(T12) or N, T² is CR^(T22) or N, T⁴ is CR^(T42) or N, T⁵ isCR^(T52) or N, T⁶ is CR^(T62) or N,

R^(T12), R^(T22), R^(T42), R^(T52) and R^(T62) are the same as ordifferent from each other, and are

H,

lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo(═O), O-(lower alkyl which may be substituted with O-(lower alkyl) orpiperidinyl (in which the piperidinyl group may be substituted withlower alkyl which may be substituted with cycloalkyl or oxo (═O))),

NH-(lower alkyl which may be substituted with O-(lower alkyl)),

cycloalkyl,

pyridyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, or oxazepanyl, each of which may be substituted withgroup(s) selected from the group consisting of OH; halogen; lower alkylwhich may be substituted with O-(lower alkyl) or oxo (═O); and O-(loweralkyl which may be substituted with O-(lower alkyl)), or

O-(tetrahydropyranyl), or

X is thiazolyl which may be substituted with morpholinyl or NH(loweralkyl which may be substituted with oxo (═O)), benzothiazolyl, orimidazo[1,2-a]pyridyl which may be substituted with lower alkyl.

(66)

(66-1) In (65-1) to (65-5), X is

or

X is

(66-2) In (65-1) to (65-5), X is

(66-3) In (66-1) to (66-2),

R^(T11), R^(T12), R^(T13), R^(T21), R^(T22), R^(T31), R^(T41), R^(T42),R^(T51), R^(T52), R^(T61), R^(T62) and R^(T63) are the same as ordifferent from each other, and are

H,

OH,

lower alkyl which may be substituted with group(s) selected from thegroup consisting of O-(lower alkyl which may be substituted withphenyl); N(lower alkyl)₂; cycloalkyl; monocyclic hetero ring group(s)which may be substituted with lower alkyl; and oxo (═O),

O-(lower alkyl which may be substituted with phenyl or oxo (═O)),

a monocyclic hetero ring group which may be substituted with group(s)selected from the group consisting of lower alkyl which may besubstituted with OH or oxo (═O); and oxo (═O),

SO₂-(lower alkyl), or

SO₂-(cycloalkyl), or

R^(T21) and R^(T31), or R^(T41) and R^(T51) may be combined with eachother to form a new bond, or

R^(T61) and R^(T62) may be combined with each other to form oxo (═O).

(66-4) In (66-1) to (66-2),

R^(T11), R^(T12), R^(T13), R^(T21), R^(T22), R^(T31), R^(T41), R^(T42),R^(T51), R^(T52), R^(T61), R^(T62) and R^(T63) are the same as ordifferent from each other, and are

H,

OH,

lower alkyl which may be substituted with group(s) selected from thegroup consisting of O-(lower alkyl which may be substituted withphenyl); N(lower alkyl)₂; cycloalkyl; pyridyl which may be substitutedwith lower alkyl; tetrahydropyranyl; and oxo (═O),

O-(lower alkyl which may be substituted with phenyl or oxo (═O)),

1,2-dihydropyridyl or pyridyl, each of which may be substituted withgroup(s) selected from the group consisting of lower alkyl which may besubstituted with OH or oxo (═O); and oxo (═O),

SO₂-(lower alkyl), or

SO₂-(cycloalkyl), or

R^(T21) and R^(T31), or R^(T41) and R may be combined with each other toform a new bond, or

R^(T61) and R^(T62) may be combined with each other to form oxo (═O).

(66-5) In (65-1) to (65-5), X is

(67)

(67-1) In (66-1) to (66-4),

T¹ is CR^(T11)R^(T12) or NR^(T13), T³ is CR^(T3), T⁵ is CR^(T51)R^(T52),T⁶ is CR^(T61)R^(T62), or NR^(T63),

R^(T11), R^(T12), R^(T13), R^(T21), R^(T22), R^(T31), R^(T41), R^(T42),R^(T51), R^(T52), R^(T61) and R^(T62) are the same as or different fromeach other, and are

H, or lower alkyl, or

R^(T61) and R^(T62) may be combined with each other to form oxo (═O),

R^(T63) is lower alkyl which may be substituted with group(s) selectedfrom the group consisting of O-(lower alkyl); N(lower alkyl)₂;cycloalkyl; hetero ring group(s) which may be substituted with loweralkyl; and oxo (═O),

a monocyclic hetero ring group which may be substituted with group(s)selected from the group consisting of lower alkyl which may besubstituted with OH or oxo (═O); and oxo (═O),

SO₂-(lower alkyl), or

SO₂-(cycloalkyl), or

R^(T21) and R^(T31), or R^(T41) and R^(T51) may be combined with eachother to form a new bond.

(67-2) In (67-1),

R^(T63) is lower alkyl which may be substituted with group(s) selectedfrom the group consisting of O-(lower alkyl); N(lower alkyl)₂;cycloalkyl; nitrogen-containing monocyclic unsaturated hetero ringgroup(s) which may be substituted with lower alkyl; monocyclic saturatedhetero ring group(s); and oxo (═O),

a nitrogen-containing monocyclic hetero ring group which may besubstituted with group(s) selected from the group consisting of loweralkyl which may be substituted with OH or oxo (═O); and oxo (═O),

SO₂-(lower alkyl), or

SO₂-(cycloalkyl).

(67-3) In (67-1) to (67-2),

R^(T63) is lower alkyl which may be substituted with group(s) selectedfrom the group consisting of O-(lower alkyl); N(lower alkyl)₂;cyclopropyl; pyridyl which may be substituted with lower alkyl;tetrahydropyranyl; and oxo (═O),

1,2-dihydropyridyl or pyridyl, each of which may be substituted withgroup(s) selected from the group consisting of lower alkyl which may besubstituted with OH or oxo (═O); and oxo (═O),

SO₂-(lower alkyl), or

SO₂-(cyclopropyl).

(67-4)

(67-4-1) In (66-1) to (66-4), and (67-1) to (67-3),

R^(T11), R^(T12), R^(T21), R^(T22), R^(T31), R^(T41) and R^(T42) are H,

R^(T51) and R^(T52) are the same as or different from each other, andare H, lower alkyl, or O-(lower alkyl),

R^(T61) and R^(T62) are the same as or different from each other, andare H, OH, O-(lower alkyl which may be substituted with aryl or oxo(═O)), or a monocyclic hetero ring group,

R^(T13) is H or lower alkyl, or

R^(T61) and R^(T62) may be combined with each other to form oxo (═O), or

R^(T21) and R^(T31), or R^(T41) and R^(T51) may be combined with eachother to form a new bond.

(67-4-2) In (66-1) to (66-4), and (67-1) to (67-3),

R^(T11), R^(T12), R^(T21), R^(T22), R^(T31), R^(T41) and R^(T42) are H,

R^(T51) and R^(T52) are the same as or different from each other, andare H, lower alkyl, or O-(lower alkyl),

R^(T61) and R^(T62) are the same as or different from each other, andare H, OH, O-(lower alkyl which may be substituted with phenyl or oxo(═O)), or a monocyclic saturated hetero ring group,

R^(T13) is H or lower alkyl, or

R^(T61) and R^(T62) may be combined with each other to form oxo (═O), or

R^(T21) and R^(T31), or R^(T41) and R^(T51) may be combined with eachother to form a new bond.

(67-4-3) In (66-1) to (66-4), and (67-1) to (67-3),

R^(T11), R^(T12), R^(T21), R^(T22), R^(T31), R^(T41) and R^(T42) are H,

R^(T51) and R^(T52) are the same as or different from each other, andare H, lower alkyl, or O-(lower alkyl),

R^(T61) and R^(T62) are the same as or different from each other, andare H, OH, O-(lower alkyl which may be substituted with phenyl or oxo(═O)), or tetrahydropyranyl,

R^(T13) is H or lower alkyl, or

R^(T61) and R^(T62) may be combined with each other to form oxo (═O), or

R^(T21) and R^(T31), or R^(T41) and R^(T51) may be combined with eachother to form a new bond.

(67-5) In (67-1) to (67-3),

R^(T11), R^(T12), R^(T21), R^(T22), R^(T31), R^(T41), R^(T42), R^(T51),R^(T52), R^(T61) and R^(T62) are H, R^(T13) is H or lower alkyl, or

R^(T61) and R^(T62) may be combined with each other to form oxo (═O), or

R^(T21) and R^(T31), or R^(T41) and R^(T51) may be combined with eachother to form a new bond.

(67-6) In (67-1) to (67-5),

T¹ is CR^(T11)R^(T12), T³ is CR^(T31), T⁵ is CR^(T51)R^(T52), and T⁶ isNR^(T63)

(67-7) In (67-1) to (67-5),

T¹ is NR^(T13), T³ is CR^(T31), T⁵ is CR^(T51)R^(T52), and T⁶ isCR^(T61)R^(T62).

(68) E is a single bond, or lower alkylene which may be substituted withoxo (═O).

(69)

(69-1) G is a single bond, O, NH, or N(lower alkyl).

(69-2) G is a single bond, O, or NH.

(70) J is a single bond or lower alkylene.

(71)

(71-1) L is O, NH, or N(lower alkyl).

(71-2) L is O or NH.

(72)

(72-1) U is a single bond, O, NH, N(lower alkyl which may be substitutedwith O-(lower alkyl)), SO₂, or lower alkylene which may be substitutedwith oxo (═O).

(72-2) U is a single bond, O, NH, N(lower alkyl), SO₂, or lower alkylenewhich may be substituted with oxo (═O).

(72-3) U is a single bond, 0, or lower alkylene.

(72-4) U is a single bond, O, NH, or N(lower alkyl which may besubstituted with O-(lower alkyl)).

(72-5) U is a single bond or O.

(73)

(73-1) V is a single bond, O, NH, N(lower alkyl), or lower alkylenewhich may be substituted with OH, O-(lower alkyl), or oxo (═O).

(73-2) V is a single bond, O, N(lower alkyl), or lower alkylene whichmay be substituted with oxo (═O).

(73-3) V is a single bond, O, or lower alkylene.

(73-4) V is a single bond or lower alkylene which may be substitutedwith OH, O-(lower alkyl), or oxo (═O).

(73-5) V is a single bond, O, or lower alkylene which may be substitutedwith oxo (═O).

(73-6) V is a single bond, or lower alkylene which may be substitutedwith oxo (═O).

(74)

(74-1) W is a single bond, SO, SO₂, or lower alkylene.

(74-2) W is a single bond, SO, or SO₂.

(74-3) W is a single bond or lower alkylene.

(74-4) W is a single bond.

(75) R¹, R², R³ and R⁴ are the same as or different from each other, andare H, halogen, or lower alkyl.

(76) R^(T61) is H.

Furthermore, other embodiments of the compound (I) of the presentinvention include compounds or salts thereof including a consistentcombination of two or more groups among the groups described in (1) to(56) above, and specifically, the following compounds or salts thereof.

(77) The compound of the formula (I), wherein A is as described in (1).

(78) The compound of the formula (I), wherein A is as described in (2).

(79) The compound as described in (77) to (78), wherein R^(Q12),R^(Q22), R^(Q42) and

R^(Q52) are as described in (4).

(80) The compound as described in (77) to (79), wherein Q¹, Q², Q⁴ andQ⁵ are as described in (6).

(81) The compound as described in (77) to (80), wherein R¹, R², R³ andR⁴ are as described in (13).

(82) The compound as described in (77) to (81), wherein E is asdescribed in (14).

(83) The compound as described in (77) to (82), wherein G is asdescribed in (16).

(84) The compound as described in (77) to (83), wherein J is asdescribed in (19).

(85) The compound as described in (77) to (84), wherein L is asdescribed in (21).

(86) The compound as described in (77) to (85), wherein U is asdescribed in (24).

(87) The compound as described in (77) to (86), wherein V is asdescribed in (27).

(88) The compound as described in (77) to (87), wherein W is asdescribed in

(28).

(89) The compound as described in (77) to (88), wherein X is asdescribed in (31).

(90) The compound as described in (89), wherein R^(T11), R^(T12),R^(T21), R^(T22), R^(T31) R^(T41), R^(T42), R^(T51) and R^(T52) are asdescribed in (33).

(91) The compound as described in (89) to (90), wherein R^(T63) is asdescribed in (39).

(92) The compound as described in (89) to (91), wherein T¹, T², T³, T⁴,T⁵ and T⁶ are as described in (40).

(93) The compound as described in (89) to (91), wherein T¹, T², T³, T⁴,T⁵ and T⁶ are as described in (41).

(94) The compound as described in (89) to (91), wherein T¹, T², T³, T⁴,T⁵ and T⁶ are as described in (42).

(95) The compound as described in (89) to (91), wherein T¹, T², T³, T⁴,T⁵ and T⁶ are as described in (43).

(96) The compound as described in (89) to (95), wherein m is asdescribed in (55).

(97) The compound as described in (89) to (95), wherein m is asdescribed in (56).

(98) The compound of the formula (I), wherein A is as described in (3).

(99) The compound as described in (77) or (98), wherein R^(Q11),R^(Q12), R^(Q13), R^(Q31), R^(Q51), R^(Q52), R^(Q53) and RQ61 are asdescribed in (5).

(100) The compound as described in (77), or (98) to (99), wherein Q¹,Q³, Q⁵ and Q⁶ are as described in (9).

(101) The compound as described in (77), or (98) to (99), wherein Q¹,Q³, Q⁵ and Q⁶ are as described in (12).

(102) The compound as described in (98) to (101), wherein R¹, R², R³ andR⁴ are as described in (13).

(103) The compound as described in (98) to (102), wherein E is asdescribed in (14).

(104) The compound as described in (98) to (103), wherein G is asdescribed in (16).

(105) The compound as described in (98) to (104), wherein J is asdescribed in (19).

(106) The compound as described in (98) to (105), wherein L is asdescribed in (21).

(107) The compound as described in (98) to (106), wherein U is asdescribed in (23).

(108) The compound as described in (98) to (107), wherein V is asdescribed in (26).

(109) The compound as described in (98) to (108), wherein W is asdescribed in (28).

(110) The compound as described in (98) to (109), wherein X is asdescribed in (31).

(111) The compound as described in (110), wherein R^(T11), R^(T12),R^(T21), R^(T22), R^(T31) R^(T41), R^(T42), R^(T51) and R^(T52) are asdescribed in (33).

(112) The compound as described in (110) to (111), wherein R^(T63) is asdescribed in (39).

(113) The compound as described in (110) to (112), wherein T¹, T², T³,T⁴, T⁵ and T⁶ are as described in (40).

(114) The compound as described in (110) to (112), wherein T¹, T², T³,T⁴, T⁵ and T⁶ are as described in (41).

(115) The compound as described in (110) to (112), wherein T¹, T², T³,T⁴, T⁵ and T⁶ are as described in (42).

(116) The compound as described in (110) to (115), wherein m is asdescribed in (55).

(117) The compound as described in (110) to (115), wherein m is asdescribed in (56).

In addition, still other embodiments of the compound (1) of the presentinvention include compounds or salts thereof including a consistentcombination of two or more groups, among the groups described in (1) to(56) and (76) above, and specifically, the following compounds or saltsthereof.

(118) The compound as described in (77) to (117), wherein R^(T61) is asdescribed in (76).

(119) The compound as described in (77) to (117), or (118), whereinR^(T62) is as described in (36) to (38).

In addition, further still other embodiments of the compound (1) of thepresent invention include compounds or salts thereof including aconsistent combination of two or more groups, among the groups describedin (1) to (76) above, and specifically, the following compounds or saltsthereof.

(120) The compound of the formula (I), wherein A is as described in (1)or (57).

(121) The compound of the formula (I), wherein A is as described in (2)or (58).

(122) The compound as described in (120) to (121), wherein R¹, R², R³and R⁴ are as described in (13) or (75).

(123) The compound as described in (120) to (122), wherein E is asdescribed in (14), (15), or (68).

(124) The compound as described in (120) to (123), wherein G is asdescribed in (16), (17), (18), or (69).

(125) The compound as described in (120) to (124), wherein J is asdescribed in (19), (20), or (70).

(126) The compound as described in (120) to (125), wherein L is asdescribed in (21), (22), or (71).

(127) The compound as described in (120) to (126), wherein U is asdescribed in (23), (24), (25), or (72).

(128) The compound as described in (120) to (127), wherein V is asdescribed in (26), (27), or (73).

(129) The compound as described in (120) to (128), wherein W is asdescribed in (28), (29), or (74).

(130) The compound as described in (120) to (129), wherein X is asdescribed in (60) or (61).

(131) The compound as described in (120) to (129), wherein X is asdescribed in (31), or (62) to (63).

(132) The compound as described in (131), wherein R^(T11), R^(T12),R^(T21), R^(T22), R^(T31) R^(T41), R^(T42), R^(T51) and R^(T52) are asdescribed in (33).

(133) The compound as described in (131) to (132), wherein R^(T61) is asdescribed in (76).

(134) The compound as described in (131) to (133), wherein R^(T62) is asdescribed in (36) to (38).

(135) The compound as described in (131) to (134), wherein R^(T63) is asdescribed in (39).

(136) The compound as described in (131) to (135), wherein T¹, T², T³,T⁴, T⁵ and T⁶ are as described in (40).

(137) The compound as described in (131) to (135), wherein T¹, T², T³,T⁴, T⁵ and T⁶ are as described in (41).

(138) The compound as described in (131) to (135), wherein T¹, T², T³,T⁴, T⁵ and T⁶ are as described in (42).

(139) The compound as described in (131) to (135), wherein T¹, T², T³,T⁴, T⁵ and T⁶ are as described in (43).

(140) The compound as described in (131) to (139), wherein m is asdescribed in (55).

(141 The compound as described in (131) to (139), wherein m is asdescribed in (56).

(142) The compound as described in (I), wherein A is as described in (3)or (59).

(143) The compound as described in (120), or (142), wherein R¹, R², R³and R⁴ are as described in (13) or (75).

(144) The compound as described in (120), or (142) to (143), wherein Eis as described in (14), (15), or (68).

(145) The compound as described in (120), or (142) to (144), wherein Gis as described in (16), (17), (18), or (69).

(146) The compound as described in (120), or (142) to (145), wherein Jis as described in (19), (20), or (70).

(147) The compound as described in (120), or (142) to (146), wherein Lis as described in (21), (22), or (71).

(148) The compound as described in (120), or (142) to (147), wherein Uis as described in (23), (24), (25), or (72).

(149) The compound as described in (120), or (142) to (148), wherein Vis as described in (26), (27), or (73).

(150) The compound as described in (120), or (142) to (149), wherein Wis as described in (28), (29), or (74).

(151) The compound as described in (120), or (142) to (150), wherein Xis as described in (60), (61), or (64).

(152) The compound as described in (120), or (142) to (150), wherein Xis as described in (31), (65) to (67).

(153) The compound as described in (152), wherein R^(T11), R^(T2),R^(T21), R^(T22), R^(T31) R^(T41), R^(T42), R^(T51) and R^(T52) are asdescribed in (33).

(154) The compound as described in (152) to (153), wherein R^(T61) is asdescribed in (76).

(155) The compound as described in (152) to (154), wherein R^(T62) is asdescribed in (36) to (38).

(156) The compound as described in (152) to (155), wherein R^(T63) is asdescribed in (39).

(157) The compound as described in (152) to (156), wherein T¹, T², T³,T⁴, T⁵ and T⁶ are as described in (40).

(158) The compound as described in (152) to (156), wherein T¹, T², T³,T⁴, T⁵ and T⁶ are as described in (41).

(159) The compound as described in (152) to (156), wherein T¹, T², T³,T⁴, T⁵ and T⁶ are as described in (42).

(160) The compound as described in (152) to (159), wherein m is asdescribed in (55).

(161) The compound as described in (152) to (159), wherein m is asdescribed in (56).

Specific examples of the compound encompassed by the present inventioninclude the following compounds or salts thereof:

-   1-carbamimidoyl-3-{3-[2-(morpholin-4-yl)pyrimidin-5-yl]benzyl}urea,-   2-fluoro-3-[2-(morpholin-4-yl)pyrimidin-5-yl]benzyl    carbamimidoylcarbamate,-   3-{2-[(3S)-3-fluoropyrrolidin-1-yl]pyrimidin-5-yl}benzyl    carbamimidoylcarbamate,-   N-{4-[2-(3-{[(carbamimidoylcarbamoyl)amino]methyl}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide,-   2-fluoro-3-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]benzyl    carbamimidoylcarbamate,-   2-fluoro-3-[4-(pyridin-4-yl)piperidin-1-yl]benzyl    carbamimidoylcarbamate,-   3-(4-{4-[5-(3-{[(carbamimidoylcarbamoyl)oxy]methyl}-2-fluorophenyl)pyrimidin-2-yl]piperazin-1-yl}phenyl)propanoic    acid,-   2-fluoro-3-{4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]piperazin-1-yl}benzyl    carbamimidoylcarbamate,-   2-fluoro-3-{4-[2-(4-hydroxy-4-methylpiperidin-1-yl)pyrimidin-5-yl]piperazin-1-yl}benzyl    carbamimidoylcarbamate,-   2-fluoro-3-(4-{2-[(3R)-3-fluoropyrrolidin-1-yl]pyrimidin-5-yl}piperazin-1-yl)benzyl    carbamimidoylcarbamate,-   2-fluoro-3-[4-(2-methoxypyrimidin-5-yl)piperazin-1-yl]benzyl    carbamimidoylcarbamate,-   3-{2-[(1-acetylpiperidin-4-yl)methoxy]pyrimidin-5-yl}-2-fluorobenzyl    carbamimidoylcarbamate,-   3-(2-{[1-(cyclopropylcarbonyl)piperidin-4-yl]methoxy}pyrimidin-5-yl)-2-fluorobenzyl    carbamimidoylcarbamate,-   2-fluoro-3-(2-{[1-(pyridin-3-ylcarbonyl)piperidin-4-yl]methoxy}pyrimidin-5-yl)benzyl    carbamimidoylcarbamate,-   2-fluoro-3-{4-[(trans-4-methoxycyclohexyl)carbonyl]piperazin-1-yl}benzyl    carbamimidoylcarbamate,-   2-fluoro-3-[4-(tetrahydro-2H-pyran-4-ylacetyl)piperazin-1-yl]benzyl    carbamimidoylcarbamate,-   3-[4-(ethylsulfonyl)piperazin-1-yl]-2-fluorobenzyl    carbamimidoylcarbamate,-   3-{4-[(1-acetylpiperidin-4-yl)oxy]piperidin-1-yl}-2-fluorobenzyl    carbamimidoylcarbamate,-   1-(3-{2-[(1-acetylpiperidin-4-yl)methoxy]pyrimidin-5-yl}-2-fluorobenzyl)-3-carbamimidoylurea,-   2-fluoro-3-[4-(pyridin-3-yl)piperazin-1-yl]benzyl    carbamimidoylcarbamate,-   2-fluoro-3-[4-(6-methylpyridin-3-yl)piperazin-1-yl]benzyl    carbamimidoylcarbamate,-   2-fluoro-3-[3-oxo-4-(pyridin-3-yl)piperazin-1-yl]benzyl    carbamimidoylcarbamate,-   2-fluoro-3-{3-[(1-propionylpiperidin-4-yl)oxy]azetidin-1-yl}benzyl    carbamimidoylcarbamate,-   2-fluoro-3-{3-[(6-methylpyridin-3-yl)oxy]azetidin-1-yl}benzyl    carbamimidoylcarbamate,-   2-fluoro-3-(3-{[6-(methoxymethyl)pyridin-3-yl]oxy}azetidin-1-yl)benzyl    carbamimidoylcarbamate,-   3-{3-[(2,6-dimethylpyridin-4-yl)methoxy]azetidin-1-yl}-2-fluorobenzyl    carbamimidoylcarbamate,-   2-fluoro-3-{4-[6-(methoxymethyl)pyridin-3-yl]piperazin-1-yl}benzyl    carbamimidoylcarbamate,-   2-fluoro-3-[4-(imidazo[1,2-a]pyridin-7-yl)piperazin-1-yl]benzyl    carbamimidoylcarbamate,-   2-fluoro-3-{3-[(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)oxy]azetidin-1-yl}benzyl    carbamimidoylcarbamate,-   2-fluoro-3-{4-[5-(methoxymethyl)pyridin-3-yl]piperazin-1-yl}benzyl    carbamimidoylcarbamate,-   2-fluoro-3-{4-[2-(2-methoxyethoxy)pyridin-4-yl]piperazin-1-yl}benzyl    carbamimidoylcarbamate,-   3-[3-(1-acetylpiperidin-4-yl)azetidin-1-yl]-2-fluorobenzyl    carbamimidoylcarbamate,-   2-fluoro-3-[3-(1-propionylpiperidin-4-yl)azetidin-1-yl]benzyl    carbamimidoylcarbamate,-   3-{3-[1-(cyclopropylcarbonyl)piperidin-4-yl]azetidin-1-yl}-2-fluorobenzyl    carbamimidoylcarbamate,-   2-fluoro-3-{3-[1-(methoxyacetyl)piperidin-4-yl]azetidin-1-yl}benzyl    carbamimidoylcarbamate,-   2-fluoro-3-{3-[1-(3-methoxypropanoyl)piperidin-4-yl]azetidin-1-yl}benzyl    carbamimidoylcarbamate,-   2-fluoro-3-{3-[1-(methylsulfonyl)piperidin-4-yl]azetidin-1-yl}benzyl    carbamimidoylcarbamate, or-   2-fluoro-3-{4-[2-(methoxymethyl)pyridin-4-yl]piperazin-1-yl}benzyl    carbamimidoylcarbamate.

The compound of the formula (I) may exist in the form of tautomers orgeometrical isomers depending on the kind of substituents. In thepresent specification, the compound of the formula (I) shall bedescribed in only one form of isomer, yet the present invention includesother isomers, an isolated form of the isomers, or a mixture thereof.

In addition, the compound of the formula (I) may have asymmetric carbonatoms or axial asymmetry in some cases, and correspondingly, it mayexist in the form of optical isomers based thereon. The presentinvention includes both an isolated form of the optical isomers of thecompound of the formula (I) or a mixture thereof.

Moreover, the present invention also includes a pharmaceuticallyacceptable prodrug of the compound represented by the formula (I). Thepharmaceutically acceptable prodrug is a compound having a group thatcan be converted into an amino group, a hydroxyl group, a carboxylgroup, or the like through solvolysis or under physiological conditions.Examples of the group forming the prodrug include the groups describedin Prog. Med., 5, 2157-2161 (1985) and “Pharmaceutical Research andDevelopment” (Hirokawa Publishing Company, 1990), Vol. 7, Drug Design,163-198.

Furthermore, the salt of the compound of the formula (I) is apharmaceutically acceptable salt of the compound of the formula (I) andmay form an acid addition salt or a salt with a base depending on thekind of substituents. Specific examples thereof include acid additionsalts with inorganic acids such as hydrochloric acid, hydrobromic acid,hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike, and with organic acids such as formic acid, acetic acid, propionicacid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleicacid, lactic acid, malic acid, mandelic acid, tartaric acid,dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, aspartic acid, glutamic acid, and the like, andsalts with inorganic bases such as sodium, potassium, magnesium,calcium, aluminum, and the like or organic bases such as methylamine,ethylamine, ethanolamine, lysine, ornithine, and the like, salts withvarious amino acids or amino acid derivatives such as acetylleucine andthe like, ammonium salts, etc.

In addition, the present invention also includes various hydrates orsolvates, and polymorphic crystalline substances of the compound of theformula (I) and salts thereof. In addition, the present invention alsoincludes compounds labeled with various radioactive or non-radioactiveisotopes.

(Preparation Methods)

The compound of the formula (I) and a salt thereof can be prepared usingthe characteristics based on the basic structure or the type ofsubstituents thereof and by applying various known synthesis methods.During the preparation, replacing the relevant functional group with asuitable protective group (a group that can be easily converted into therelevant functional group) at the stage from starting material to anintermediate may be effective depending on the type of the functionalgroup in the production technology in some cases. The protective groupfor such a functional group may include, for example, the protectivegroups described in “Greene's Protective Groups in Organic Synthesis(4^(th) edition, 2006)”, P. G. M. Wuts and T. W. Greene, and one ofthese may be selected and used as necessary depending on the reactionconditions. In this kind of method, a desired compound can be obtainedby introducing the protective group, by carrying out the reaction and byeliminating the protective group as necessary.

In addition, the prodrug of the compound of the formula (I) can beprepared by introducing a specific group at the stage from a startingmaterial to an intermediate, as in the case of the above-mentionedprotective group, or by carrying out the reaction using the obtainedcompound of the formula (I). The reaction can be carried out usingmethods known to those skilled in the art, such as ordinaryesterification, amidation, dehydration, and the like.

Hereinbelow, the representative preparation methods for the compound ofthe formula (I) will be described. Each of the production processes mayalso be carried out with reference to the References appended in thepresent description. Further, the preparation methods of the presentinvention are not limited to the examples as shown below. Further,depending on the compounds, the preparation method can be carried outwhile changing the sequence of the production processes.

(Production Process 1)

The compound (1) of the present invention can be obtained by thecondensation of the compound (29) with guanidine in the presence of1,1′-carbonyldiimidazole (CDI).

In this reaction, the compound (29) and guanidine in an equivalentamount or an excess amount are used, and a mixture thereof is stirred ina range of from cooling to heating, preferably at −20° C. to 60° C.,usually for about 0.1 hours to 5 days, in a solvent which is inert tothe reaction, in the presence of CDI. The solvent as used herein is notparticularly limited, but examples thereof include aromatic hydrocarbonssuch as benzene, toluene, xylene, and the like, halogenated hydrocarbonssuch as dichloromethane, 1,2-dichloroethane, chloroform, and the like,ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane,and the like, DMF, DMSO, EtOAc, acetonitrile, or water, and a mixturethereof. It may be in some cases advantageous for smooth progress of thereaction to carry out the reaction in the presence of organic bases suchas triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, DBU,and the like, or inorganic bases such as sodium hydride, potassiumcarbonate, sodium carbonate, potassium hydroxide, and the like.

[Document]

Synthesis 2006, 4, 629-632

(Starting Material Synthesis 1)

The compound (2) can be obtained by the bromination reaction of thecompound (1).

For the bromination reaction, the compound (1) and a brominating agentin an equivalent amount or an excess amount are used, and a mixturethereof is stirred in a range of from cooling to heating and refluxing,preferably at −20° C. to 200° C., and more preferably at a temperaturefrom −10° C. to 150° C., usually for about 0.1 hours to 5 days, withouta solvent or in a solvent which is inert to the reaction. The solvent asused herein is not particularly limited, but examples thereof includealcohols such as methanol, ethanol, tert-butanol, and the like, etherssuch as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, andthe like, halogenated hydrocarbons such as dichloromethane,1,2-dichloroethane, chloroform, and the like, N,N-dimethylformamide,dimethylsulfoxide, and a mixture thereof. It may be in some casesadvantageous for smooth progress of the reaction to carry out thereaction in the presence of a Lewis acid such as aluminum chloride(AlCl₃), boron trifluoride (BF₃), and the like, or a radical initiatorsuch as α,α′-azobisisobutyronitrile (AIBN) and the like. Examples of thebrominating reagent include N-bromosuccinimide, in addition to bromine(Br₂).

(Starting Material Synthesis 2)

The compound (4) can be obtained by the reduction reaction of a compound(3). In this reaction, the compound (3) is treated by using a reducingagent in an equivalent amount or an excess amount, or a metalliccatalyst in a catalytic amount or an excess amount in a range of fromcooling to heating, preferably at −20° C. to 80° C., usually for about0.1 hours to 3 days, in a solvent which is inert to the reaction. Thesolvent as used herein is not particularly limited, but examples thereofinclude ethers such as diethyl ether, tetrahydrofuran, dioxane,dimethoxyethane, and the like, alcohols such as methanol, ethanol,2-propanol, and the like, aromatic hydrocarbons such as benzene,toluene, xylene, and the like, N,N-dimethylformamide, dimethylsulfoxide,ethyl acetate, and a mixture thereof. As the reducing agent, metalreducing agents such as zinc, iron, tin, and the like, and reducingagents described in the documents below are suitably used.Alternatively, in the reaction using a metal catalyst such as palladium,platinum, and the like, hydrogen gas atmosphere or ammonium formate isused as a hydrogen source.

[Documents]

M. Hudlicky, “Reductions in Organic Chemistry, 2^(nd) Ed. (ACSMonograph: 188)”, ACS, 1996

R. C. Larock, “Comprehensive Organic Transformations”, 2^(nd) Ed., VCHPublishers, Inc., 1999

T. J. Donohoe, “Oxidation and Reduction in Organic Synthesis (OxfordChemistry Primers 6)”, Oxford Science Publications, 2000 “Jikken KagakuKoza” (Courses in Experimental Chemistry) (5^(th) Edition), edited byThe Chemical Society of Japan, Vol. 14 (2005) (Maruzen)

The compound (42) can be obtained by subjecting the compound (4) to aSandmeyer's Reaction.

In this reaction, the compound (4) is converted into a diazonium salt byreaction of the compound (4) in the presence of hydrogen halide andsodium nitrite in an equivalent amount or an excess amount, in a rangeof from cooling to heating, preferably at −20° C. to 80° C., usually forabout 0.1 hours to 3 days, in a solvent which is inert to the reaction.The solvent as used herein is not particularly limited, but examplesthereof include ethers such as diethyl ether, tetrahydrofuran, dioxane,dimethoxyethane, and the like, alcohols such as methanol, ethanol,2-propanol, and the like, aromatic hydrocarbons such as benzene,toluene, xylene, and the like, N,N-dimethylformamide, dimethylsulfoxide,ethyl acetate, and a mixture thereof. Next, the compound (42) can beobtained by reaction of the obtained diazonium salt of the compound (4)in the presence of copper (I) halide in an equivalent amount or anexcess amount, in a range of from room temperature to heating,preferably at −20° C. to 80° C., usually for about 0.1 hours to 3 days,in a solvent which is inert to the reaction. The solvent as used hereinis not particularly limited, but examples thereof include ethers such asdiethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like,alcohols such as methanol, ethanol, 2-propanol, and the like, aromatichydrocarbons such as benzene, toluene, xylene, and the like,N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate, and a mixturethereof. Further, examples of the copper (I) halide as used hereininclude copper (I) chloride and copper (I) bromide.

(Starting Material Synthesis 3)

(wherein E¹ represents lower alkylene which may be substituted having anumber of carbon atoms one less than that of carbon atoms in loweralkylene which may be substituted in E).

The compound (6) can be obtained by the reduction reaction of thecompound (5). In this reduction reaction, the compound (5) is convertedinto an ester or treated with CDI, and then treated with a reducingagent in an equivalent amount or an excess amount in a range of fromcooling to heating, preferably at −78° C. to 120° C., usually for about0.1 hours to 3 days, in a solvent which is inert to the reaction. Thesolvent as used herein is not particularly limited, but examples thereofinclude ethers such as diethyl ether, tetrahydrofuran, dioxane,dimethoxyethane, and the like, aromatic hydrocarbons such as benzene,toluene, xylene, and the like, and a mixture thereof. As the reducingagent, sodium borohydride, diisobutylaluminum hydride, or the like issuitably used.

A compound (7) can be obtained by the hydrolysis reaction of a compound(6).

In this hydrolysis reaction, the compound (6) is treated with an acid orbase in an equivalent amount or an excess amount in a range of fromcooling to heating, preferably at 25° C. to 120° C., usually for about0.1 hours to 3 days, in a solvent which is inert to the reaction. Thesolvent as used herein is not particularly limited, but examples thereofinclude ethers such as diethyl ether, tetrahydrofuran, dioxane,dimethoxyethane, and the like, aromatic hydrocarbons such as benzene,toluene, xylene, and the like, N,N-dimethylformamide, dimethylsulfoxide,water, and a mixture thereof. As the acid, for example, hydrochloricacid, sulfuric acid, or the like is suitably used. As the base, sodiumhydroxide, lithium hydroxide, or the like is suitably used, and thereaction is carried out in the presence of hydrogen peroxide, it maybeadvantageous in the reaction to proceed smoothly.

[Documents]

B. M. Trost, “Comprehensive Organic Synthesis”, Vol. 7, 1991

M. Hudlicky, “Oxidation in Organic Chemistry (ACS Monograph: 186)”, ACS,1990

“Jikken Kagaku Koza” (Courses in Experimental Chemistry) (5^(th)Edition), edited by The Chemical Society of Japan, Vol. 17 (2005)(Maruzen)

(Starting Material Synthesis 4)

(wherein Lv represents a leaving group, K represents CH₂ or C(═O), andwhen K is C(═O), L represents O).

A compound (10) can be synthesized by subjecting the compound (8) to aWittig reaction. Here, examples of the leaving group, Lv, includehalogen, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, andthe like.

In this reaction, the compound (8) is converted into a phosphonium saltin the presence of a phosphorous compound in an equivalent amount or inan excess amount in a range of from cooling to heating, preferably at−20° C. to 150° C., usually for about 0.1 hours to 3 days, in a solventwhich is inert to the reaction. The solvent as used herein is notparticularly limited, but examples thereof include ethers such asdiethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like,aromatic hydrocarbons such as benzene, toluene, xylene, and the like,N,N-dimethylformamide, dimethylsulfoxide, and a mixture thereof. As thephosphorous compound, for example, an alkyltriphenylphosphonium salt issuitably used, and specific examples thereof include(methoxymethyl)triphenylphosphonium chloride,(methylthiomethyl)triphenylphosphonium chloride, and the like.Thereafter, the phosphonium salt of the compound (8) and the compound(9) are converted into the compound (10) by treating them in a range offrom cooling to heating, preferably at −20° C. to 80° C., usually forabout 0.1 hours to 3 days, in a solvent which is inert to the reaction.The solvent as used herein is not particularly limited, but examplesthereof include ethers such as diethyl ether, tetrahydrofuran, dioxane,dimethoxyethane, and the like, aromatic hydrocarbons such as benzene,toluene, xylene, and the like, N,N-dimethylformamide, dimethylsulfoxide,and a mixture thereof. It may be in some cases advantageous for smoothprogress of the reaction to carry out the reaction in the presence of abase such as sodium bis(trimethylsilyl)amide, n-butyllithium, potassiumtert-butoxide, sodium ethoxide, sodium methoxide, and the like.

The compound (11) can be obtained by the hydrogenation reaction of thecompound (10).

In this reaction, the compound (10) is stirred under hydrogenatmosphere, preferably at normal pressure to 3 atm., in a range of fromcooling to heating, preferably at room temperature to 50° C., usuallyfor about 1 hour to 5 days, in the presence of a metallic catalyst, in asolvent which is inert to the reaction. The solvent as used herein isnot particularly limited, but examples thereof include alcohols such asmethanol, ethanol, 2-propanol, and the like, ethers such as diethylether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, water,ethyl acetate, N,N-dimethylformamide, dimethylsulfoxide, and a mixturethereof. As the metal catalyst, palladium catalysts such as palladiumcarbon, palladium black, palladium hydroxide, and the like, platinumcatalysts such as a platinum plate, platinum oxide, and the like, nickelcatalysts such as reduced nickel, Raney nickel, and the like, rhodiumcatalysts such as tetrakistriphenylphosphine chlororhodium, and thelike, or iron catalysts such as reduced iron and the like are suitablyused. Instead of the hydrogen gas, formic acid or ammonium formate in anequivalent amount or an excess amount may also be used as a hydrogensource, relative to the compound (10).

[Documents]

M. Hudlicky, “Reductions in Organic Chemistry, 2^(nd) ed (ACS Monograph:188)”, ACS, 1996

“Jikken Kagaku Koza” (Courses in Experimental Chemistry) (5^(th)Edition), edited by The Chemical Society of Japan, Vol. 19 (2005)(Maruzen)

(Starting Material Synthesis 5)

(wherein G¹ represents O, NH, N(lower alkyl which may be substituted)).

The compound (14) can be obtained by the substitution reaction of thecompound (12) and the compound (13).

In this reaction, the compound (12) and the compound (13) in anequivalent amount or an excess amount are used, a mixture thereof isstirred in a range of from cooling to heating and refluxing, preferablyat 0° C. to 200° C., and more preferably at 60° C. to 150° C., usuallyfor 0.1 hours to 5 days in a solvent which is inert to the reaction orwithout a solvent. It is in some cases advantageous for smooth progressof the reaction to carry out the reaction under irradiation withmicrowaves. The solvent used herein is not particularly limited, butexamples thereof include alcohols such as methanol, ethanol,tert-butanol, and the like, aromatic hydrocarbons such as benzene,toluene, xylene, and the like, ethers such as diethyl ether,tetrahydrofuran, dioxane, dimethoxyethane, and the like, halogenatedhydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform,and the like, N,N-dimethylformamide, dimethylsulfoxide, ethyl acetate,acetonitrile, and a mixture thereof. It may be advantageous in somecases for the smooth progress of the reaction to carry out the reactionin the presence of an organic base such as triethylamine,N,N-diisopropylethylamine, N-methylmorpholine, and the like, or aninorganic base such as sodium tert-butoxide, potassium carbonate, sodiumbis(methylsilyl)amide, sodium carbonate, potassium hydroxide, sodiumhydride and the like.

Furthermore, the reaction may be carried out by using a catalyst whichis not particularly limited, but includes catalysts used for Ullmannreaction, a Buchwald-Hartwig reaction, or the like. The catalyst as usedherein is not particularly limited, but a suitable combination oftris(dibenzylideneacetone)dipalladium,tetrakis(triphenylphosphine)palladium, or the like with1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine),4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene (Xantphos),2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos), and thelike can be used.

[Documents]

S. R. Sandler and W. Karo, “Organic Functional Group Preparations”,2^(nd) Ed., Vol. 1, Academic Press Inc., 1991

“Jikken Kagaku Koza” (Courses in Experimental Chemistry) (5^(th)Edition), edited by The Chemical Society of Japan, Vol. 14 (2005)(Maruzen) Synthesis 2006, 4, 629 to 632

(Starting Material Synthesis 6)

The compound (16) can be obtained by the substitution reaction of thecompound (15) and the compound (13). This reaction can be carried outusing the same conditions as for the substitution reaction in StartingMaterial Synthesis 5.

(Starting Material Synthesis 7)

The compound (18) can be obtained by the reduction reaction of thecompound (17). The present reaction can be carried out using the samereaction conditions in Starting Material Synthesis 3. As the reducingagent in the present reaction, lithium aluminum hydride, borane, sodiumborohydride, diisobutylaluminum hydride, or the like can be used.

(Starting Material Synthesis 8)

(R^(B1) and R^(B2) are the same as or different from each other, and areH or lower alkyl, or R^(B1) and R^(B2) are combined with each other torepresent lower alkylene).

The compound (20) can be obtained by formation reaction of boronateester of the compound (19).

For the reaction, a mixture of the compound (19) and the reagent for theformation of boronate ester in an equivalent amount or an excess amountis stirred in a range of from cooling to heating, preferably at −20° C.to 60° C., usually for about 0.1 hours to 5 days, in a solvent which isinert to the reaction, in the presence of an organic metal compound. Thesolvent as used herein is not particularly limited, but examples thereofinclude aromatic hydrocarbons such as benzene, toluene, xylene, and thelike, halogenated hydrocarbons such as dichloromethane,1,2-dichloroethane, chloroform, and the like, ethers such as diethylether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, DMF,DMSO, EtOAc, acetonitrile, water, and a mixture thereof. Examples of thereagent for the formation of boronate ester include triisopropyl borate,tributyl borate, and the like. Examples of the organic metal compound asused in the present reaction include organic lithium compounds such asn-butyl lithium and the like.

Furthermore, the compound (22) can be obtained by the coupling reactionof the compound (20) and the compound (21).

In this reaction, a mixture of the compound (20) and the compound (21)in an equivalent amount or an excess amount is stirred in a range offrom cooling to heating and refluxing, and preferably 0° C. to 80° C.,in a solvent which is inert to the reaction or without a solvent,usually for 0.1 hours to 5 days. The solvent as used herein is notparticularly limited, but examples thereof include aromatic hydrocarbonssuch as benzene, toluene, xylene, and the like, ethers such as dimethylether, diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and thelike, halogenated hydrocarbons such as dichloromethane,1,2-dichloroethane, chloroform, and the like, N,N-dimethylformamide,dimethylsulfoxide, ethyl acetate, acetonitrile and a mixture thereof. Itmay be in some cases advantageous for smooth progress of the reaction tocarry out the reaction in the presence of organic bases such astriethylamine, N,N-diisopropylethylamine, N-methylmorpholine, and thelike, or inorganic bases such as potassium carbonate, sodium carbonate,potassium phosphate, potassium hydroxide, and the like.

Furthermore, the reaction can also be carried out using, for example, acatalyst used for the Suzuki-Miyaura cross-coupling reaction, but is notlimited thereto. The catalyst as used herein is not particularlylimited, but tetrakis(triphenylphosphine)palladium (0), palladiumacetate (II),dichloro[1,1′-bis(diphenylphosphenylphosphino)ferrocene]palladium (II),bistriphenylphosphine palladium chloride (II), or the like can be used.Further, the coupling reaction can also be carried out using metalpalladium (0).

(Starting Material Synthesis 9)

The compound (24) can be prepared by formation reaction of boronateester of the compound (23). This reaction can be carried out using thesame reaction conditions as in Starting Material Synthesis 8 asdescribed above.

The compound (25) can be obtained by the coupling reaction of thecompound (24) and the compound (21). This reaction can be carried outusing the same reaction conditions as in Starting Material Synthesis 8as described above.

Furthermore, a compound (26) can be obtained by the reduction reactionof the compound (25). In this reduction reaction, the compound (25) istreated with a reducing agent in an equivalent amount or an excessamount in a range of from cooling to heating, preferably at −78° C. to120° C., usually for about 0.1 hours to 3 days, in a solvent which isinert to the reaction. The solvent as used herein is not particularlylimited, but examples thereof include ethers such as diethyl ether,tetrahydrofuran, dioxane, dimethoxyethane, and the like, aromatichydrocarbons such as benzene, toluene, xylene, and the like, and amixture thereof. As the reducing agent, sodium borohydride,diisobutylaluminum hydride, or the like is suitably used.

(Starting Material Synthesis 10)

The compound (29) can be obtained by the substitution reaction of thecompound (27) and the compound (28). This reaction can be carried outusing the same reaction conditions in Starting Material Synthesis 5.

(Starting Material Synthesis 11)

The compound (30) can be prepared by the boronic acid esterificationreaction of the compound (29). This reaction can be carried out usingthe same reaction conditions as in Starting Material Synthesis 8 asdescribed above.

The compound (31) can be obtained by the hydrolysis reaction of thecompound (30).

In this reaction, a mixture of the compound (30) and water in anequivalent amount or an excess amount is stirred in a range of fromcooling to heating and refluxing, preferably at 0° C. to 80° C., usuallyfor about 0.1 hours to 5 hours, in a solvent which is inert to thereaction or without a solvent. The solvent as used herein is notparticularly limited, but examples thereof include aromatic hydrocarbonssuch as benzene, toluene, xylene, and the like, ethers such as dimethylether, diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and thelike, halogenated hydrocarbons such as dichloromethane,1,2-dichloroethane, chloroform, and the like, N,N-dimethylformamide,dimethylsulfoxide, ethyl acetate, acetonitrile, and a mixture thereof.Examples of the oxidant include sodium perborate.hexahydrate, aqueoushydrogen peroxide, and the like.

(Starting Material Synthesis 12)

represents a nitrogen-containing hetero ring group which may besubstituted, and the substituent represents an acceptable substituent inthe hetero ring group which may be substituted in A).

The compound (35) can be obtained by the substitution reaction of thecompound (33) and the compound (34). This reaction can be carried outusing the same conditions as for the substitution reaction in StartingMaterial Synthesis 5.

(Starting Material Synthesis 13)

The compound (38) can be obtained by the substitution reaction of thecompound (36) and the compound (37). This reaction can be carried outusing the same conditions as for the substitution reaction in StartingMaterial Synthesis 5.

(Starting Material Synthesis 14)

(wherein in the formula:

M¹ is a single bond or CR^(M11)R^(M12), M³ is CR^(M31) or N, M⁵ is asingle bond or (CR^(M51)R^(M52))_(n), M⁶ is CR^(M61)R^(M62), O, orNR^(M63), wherein either one of M³ and M⁶ is N, R^(M11), R^(M12),R^(M21), R^(M22), R^(M31), R^(M41), R^(M42), R^(M51), R^(M52), R^(M61),R^(M62) and R^(M63) are the same as or different from each other, andare H, OH, halogen, lower alkyl which may be substituted, O-(lower alkylwhich may be substituted), or SO₂-(lower alkyl which may besubstituted), or R^(M21) and R^(M31) may be combined with each other toform a new bond, or R^(M11) and R^(M12), R^(M21) and R^(M22), R^(M41)and R^(M42), R^(M51) and RM⁵², or R^(M61) and R^(M62) may be combinedwith each other to form oxo (═O), and n is 1 or 2).

The compound (41) among the compounds (37) can be obtained by thesubstitution reaction of the compound (39) and the compound (40). Thisreaction can be carried out using the same conditions as for thesubstitution reaction in Starting Material Synthesis 5.

The compounds of the formula (I) can be isolated and purified as theirfree compounds, salts, hydrates, solvates, or polymorphic crystallinesubstances thereof. The salts of the compound of the formula (I) can beprepared by carrying out the treatment of a conventional salt formingreaction.

Isolation and purification are carried out by employing ordinarychemical operations such as extraction, fractional crystallization,various types of fractional chromatography, and the like.

Various isomers can be prepared by selecting an appropriate startingcompound or separated by using the difference in the physicochemicalproperties between the isomers. For example, the optical isomers can beobtained by means of a general method for designing optical resolutionof racemic products (for example, fractional crystallization forinducing diastereomer salts with optically active bases or acids,chromatography using a chiral column or the like, and others), andfurther, the isomers can also be prepared from an appropriate opticallyactive starting compound.

The pharmacological activity of the compound of the formula (I) wasconfirmed by the tests shown below.

TEST EXAMPLE 1 Inhibitory Effect on Human VAP-1 Enzyme (SSAO) Activity

A human VAP-1 enzyme (SSAO) (reference: J Exp Med. 1998 Jul. 6; 188(1):17 to 27) activity was measured by a radiochemistry-enzymatic assayusing ¹⁴C-benzylamine as an artificial substrate. After homogenizing CHO(Chinese Hamster Ovary) cells stably expressing a human VAP-1 enzyme(SSAO) in a 50 mM phosphate buffer containing 1% NP-40, an enzymesuspension was obtained by taking the supernatant obtained bycentrifugation. The enzyme suspension was preincubated with the compoundof the present invention in a 96-well microplate at room temperature for30 minutes. Subsequently, the enzyme suspension was incubated with¹⁴C-benzylamine (a final concentration of 1×10⁻⁵ mol/L) to a finalvolume of 50 mL at 37° C. for 1 hour. The enzymatic reaction was stoppedby the addition of 2 mol/L (50 μL) of citric acid. The oxidationproducts were extracted directly into a 200 μL toluene scintillator, andthe radioactivity was measured with a scintillation spectrometer.

TEST EXAMPLE 2 Inhibitory Effect on Rat VAP-1 Enzyme (SSAO) Activity

A rat VAP-1 enzyme (SSAO) (reference: Biol Pharm Bull. 2005 March;28(3): 413-8) activity was measured by a radiochemistry-enzymatic assayusing ¹⁴C-benzylamine as an artificial substrate. After homogenizing CHO(Chinese Hamster Ovary) cells stably expressing a rat VAP-1 enzyme(SSAO) in a 50 mM phosphate buffer containing 1% NP-40, an enzymesuspension was obtained by taking the supernatant obtained bycentrifugation. The enzyme suspension was preincubated with the compoundof the present invention in a 96-well microplate at room temperature for30 minutes. Subsequently, the enzyme suspension was incubated with¹⁴C-benzylamine (a final concentration of 1×10⁻⁵ mol/L) to a finalvolume of 50 mL at 37° C. for 1 hour. The enzymatic reaction was stoppedby the addition of 2 mol/L (50 μL) of citric acid. The oxidationproducts were extracted directly in a 200 μL toluene scintillator, andthe radioactivity was measured with a scintillation spectrometer.

The results are shown in Table 1. In addition, the inhibitory activityis expressed as an IC₅₀ (nmol/L) value. Further, Ex in the tablesrepresents Example No.

TABLE 1 human rat Ex (nM) (nM) 11 5.2 2.2 29 7.2 1.9 52 23 1.7 63 3.41.1 74 5.3 1.8 81 9.7 3.9 83 25 1.9 105 14 2.6 110 32 1.4 118 29 1.7 12615 0.53 157 49 2.1 178 33 4.4 220 25 1 273 19 0.95 293 19 0.97 300 191.7 304 34 6.6 316 11 0.9 322 51 22 335 11 2 551 14 1.8 552 25 5.5 55320 3 554 21 0.97 555 20 3.5 556 2.7 1.3 557 11 1.6 558 23 1.2 559 4.30.81 560 9 1.4 561 9.6 1.6 562 14 1.4 563 20 1.5 564 19 1.5 565 19 2.5566 6.3 1.2 567 4.3 0.81

From these test, it was confirmed that the compound of the presentinvention has an extremely high inhibitory activity on human and ratVAP-1.

TEST EXAMPLE 3 Inhibitory Effect on Rat VAP-1 Enzyme (SSAO) Activity inRat Plasma

Eight-week to twelve-week Wistar male rats were fasted for 20 hours, andorally administered with a test drug (0.3 mg/1 kg). Heparin bloodcollection from the tail vein was performed immediately before theadministration, and at 1 h, 3 h, 6 h, 12 h, or 24 h after theadministration. The resulting blood was subjected to centrifugation at14000 rpm for 5 minutes to separate plasma, and the VAP-1 enzymeactivity in the resulting plasma was measured by a radio-enzyme assaymethod.

For the radio-enzyme assay method, ¹⁴C-benzylamine which is a syntheticsubstrate (10 μM) was reacted with the resulting plasma at 37° C., andthe resulting metabolite was extracted with a mixture of toluene/ethylacetate. The radioactivity was measured and taken as a VAP-1 enzymeactivity in the plasma. The effect of the test drug was calculated fromthe inhibitory ratio (%) of the VAP-1 activity after the administrationof the test drug relative to the VAP-1 activity in the plasmaimmediately before the administration. Further, Ex in the tablesrepresents Example No.

Reference Document Diabetologia (1997) 40 1243-1250

TABLE 2 Inhibition Ratio (%) Ex 1 h 3 h 6 h 12 h 24 h 11 64 70 63 12 2946 60 58 22 52 90 68 52 37 63 83 87 80 68 74 79 74 81 40 81 78 78 78 5383 34 66 86 53 105 22 38 31 6 110 96 96 95 75 118 87 86 88 59 126 98 9797 69 157 95 91 80 39 178 63 73 67 80 220 80 80 84 27 273 55 74 54 19293 59 83 72 60 300 92 93 88 85 304 52 56 56 18 316 91 99 98 91 322 4055 50 38 335 82 84 86 83 551 68 59 51 5 552 93 81 75 24 553 67 57 50 40554 99 100 87 72 555 67 69 54 27 556 55 70 46 19 557 53 71 56 22 558 8487 81 62 559 86 89 82 59 560 89 91 84 58 561 91 92 85 64 562 79 81 78 37563 69 77 70 43 564 89 90 85 59 565 77 83 71 47 566 75 74 70 38 567 8689 82 59

TEST EXAMPLE 4 Effect on Albuminuria in Rats with Diabetes Mellitus

Seven- to eight-week SD rats (having weights up to 200 to 250 g duringfasting) were used and fasted for 20 hours, and then intraperitoneallyadministered with 60 mg/ml/kg of streptozotocin (STZ) prepared with a 2mmol/1 citric acid buffer (pH 4.5). At the same time, the control ratswere injected with the same amount of a 2 mmol/1 citric acid buffer (pH4.5). The blood glucose value was measured using a colorimetric method,and the rats that had showed a value of 350 mg/dl blood glucose levelson day 3 after the treatment with STZ were diagnosed with diabetesmellitus.

The test substance was given daily for 4 weeks after the treatment withSTZ. After 4 weeks of the treatment with the test substance, 24-hoururine collection was performed using metabolic cages.

The amounts of urinary albunmin excretion after 4 weeks were 67 (mg/gCr)and 236 (mg/gCr) with the control group and the STZ-treated group,respectively, and the amount of urinary albunmin excretion of theSTZ-treated group increased 3.5 times than that of the control group. Onthe other hand, as a result of the oral administration of the compoundof Example 11 in the amount of 0.3 mg/kg once daily, an amount ofurinary albunmin excretion was 103 (mg/gCr), which was decreased to 1.5times than that of the control group.

Furthermore, in the test with the compound of Example 557, the amount ofurinary albunmin excretion after 4 weeks were 45 (mg/gCr) and 234(mg/gCr) with the control group and the STZ-treated group, respectively,and the amount of urinary albunmin excretion of the STZ-treated groupwas increased to 5.2 times than that of the control group. On the otherhand, as a result of the oral administration of the compound of Example557 in the amount of 0.3 mg/kg once daily, amount of urinary albunminexcretion was 105 (mg/gCr), which was decreased to 2.3 times than thatof the control group.

TEST EXAMPLE 5 Effect on Eye Permeability in Rats with Diabetes Mellitus

Seven-week Long-Evans rats (having weights up to 200 to 250 g duringfasting) were used and fasted for 20 hours, and then intraperitoneallyadministered with 60 mg/ml/kg of streptozotocin (STZ) prepared with a 2mmol/1 citric acid buffer (pH 4.5). At the same time, the control ratswere injected with the same amount of a 2 mmol/1 citric acid buffer (pH4.5). The blood glucose value was measured using a colorimetric method,and the rats that had showed a value of 350 mg/dl blood glucose levelson day 3 after the treatment with STZ were diagnosed with diabetesmellitus.

The test substance was given daily for 2 weeks after the treatment withSTZ. After 2 weeks of the treatment with the test substance, the retinalvascular permeability was examined after 24 hours from the date of thefinal administration. The retinal permeability was examined on the basisof the dye leakage into the retina after 2 h from the tail veinadministration of 40 mg/ml/kg of Evans Blue Dye solution. Thepermeability as an index of the evaluation was expressed in the ratio ofthe retinal concentration/plasma concentration of the Evans Blue Dye.Measurement of the Evans Blue Dye concentration was carried out bymeasuring the absorbance using a plate reader.

After the result of the tests above, it was confirmed that some of thecompounds of the formula (I) constantly exhibit a VAP-1 activity inblood in the oral administration test with rats. Therefore, thecompounds can be used for treatment of VAP-1-related diseases or thelike.

In the present specification, the thermal analysis measurement wascarried out in the following order.

(Differential Scanning Calorimetry (DSC Analysis))

The DSC analysis was carried out using a Q1000 manufactured by TAInstruments. Approximately 2 mg of a sample was charged in anexclusively-used aluminum-made sample pan, and the change in heat amountgenerated between the sample and a reference (an empty aluminum samplepan), with a measurement range from room temperature to 300° C. undernitrogen atmosphere (50 mL/min) and a temperature elevating rate of 10°C./min were continuously measured and recorded. Furthermore, the devicesincluding data processing was handled in accordance to the methods andprocedures as instructed in each device.

Furthermore, the term “around” as used in the values of the endothermiconset temperature in DSC largely means the values of the temperature ofthe endothermic onset (extrapolation initiation), preferably, it meansthat the values be not more or less than the values by 2° C., and morepreferably, it means that the values be not more or less than the valuesby 1° C.

A pharmaceutical composition containing one or two or more kinds of thecompound of the formula (I) or a salt thereof as an active ingredientcan be prepared using excipients that are usually used in the art, thatis, excipients for pharmaceutical preparations, carriers forpharmaceutical preparations, and the like according to the methodsusually used.

Administration can be accomplished either by oral administration viatablets, pills, capsules, granules, powders, solutions, and the like, orparenteral administration, such as injections such as intraarticular,intravenous, and intramuscular injections, suppositories, ophthalmicsolutions, eye ointments, transdermal liquid preparations, ointments,transdermal patches, transmucosal liquid preparations, transmucosalpatches, inhalers, and the like.

The solid composition for use in the oral administration is used in theform of tablets, powders, granules, or the like. In such a solidcomposition, one or more active ingredient(s) are mixed with at leastone inactive excipient. In a conventional method, the composition maycontain inactive additives, such as a lubricant, a disintegrating agent,a stabilizer, or a solubilization assisting agent. If necessary, tabletsor pills may be coated with sugar or a film of a gastric or entericcoating substance.

The liquid composition for oral administration contains pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, elixirs, or thelike, and also contains generally used inert diluents, for example,purified water or ethanol. In addition to the inert diluent, the liquidcomposition may also contain auxiliary agents, such as a solubilizationassisting agent, a moistening agent, and a suspending agent, sweeteners,flavors, aromatics, or antiseptics.

The injections for parenteral administration include sterile aqueous ornon-aqueous solutions, suspensions and emulsions. The aqueous solventincludes, for example, distilled water for injection and physiologicalsaline. Examples of the non-aqueous solvent include alcohols such asethanol. Such a composition may further contain a tonicity agent, anantiseptic, a moistening agent, an emulsifying agent, a dispersingagent, a stabilizer, or a solubilizing aid. These are sterilized, forexample, by filtration through a bacteria retaining filter, by blendinga bactericide, or irradiation. In addition, these can also be used bypreparing a sterile solid composition, and dissolving or suspending itin sterile water or a sterile solvent for injection prior to its use.

The agent for external use includes ointments, plasters, creams,jellies, poultices, sprays, lotions, eye drops, eye ointments, and thelike. The agents contain generally used ointment bases, lotion bases,aqueous or non-aqueous liquid preparations, suspensions, emulsions, andthe like.

As the transmucosal agents such as an inhaler, a transnasal agent, andthe like, those in the form of a solid, liquid, or semi-solid state areused, and can be prepared in accordance with a conventionally knownmethod. For example, a known excipient, and also a pH adjusting agent,an antiseptic, a surfactant, a lubricant, a stabilizer, a thickeningagent, or the like may be appropriately added thereto. For theiradministration, an appropriate device for inhalation or blowing can beused. For example, a compound may be administered alone or as a powderof formulated mixture, or as a solution or suspension in combinationwith a pharmaceutically acceptable carrier, using a known device orsprayer, such as a measured administration inhalation device, and thelike. A dry powder inhaler or the like may be for single or multipleadministration use, and a dry powder or a powder-containing capsule maybe used. Alternatively, this may be in a form such as a pressurizedaerosol spray which uses an appropriate ejection agent, for example, asuitable gas such as chlorofluoroalkane, carbon dioxide, and the like.

In oral administration, the daily dose is generally from about 0.001 to100 mg/kg, preferably from 0.1 to 30 mg/kg, and more preferably 0.1 to10 mg/kg, per body weight, administered in one portion or in 2 to 4separate portions. In the case of intravenous administration, the dailydose is suitably administered from about 0.0001 to 10 mg/kg per bodyweight, once a day or two or more times a day. In addition, atransmucosal agent is administered at a dose from about 0.001 to 100mg/kg per body weight, once a day or two or more times a day. The doseis appropriately decided upon in response to the individual case bytaking the symptoms, the age, and the gender, and the like intoconsideration.

The compound of the formula (I) can be used in combination with varioustherapeutic or prophylactic agents for the diseases for which thecompound of the formula (I) is considered to be effective, as describedabove. The combined preparation may be administered simultaneously, orseparately and continuously, or at a desired time interval. Thepreparations to be administered simultaneously may be a blend, or may beprepared individually.

EXAMPLES

Hereinbelow, the preparation methods for the compound of the formula (I)will be described in more detail with reference to Examples. Further,the present invention is not limited to only the preparation methods ofthe specific Examples and Preparation Examples are shown below, but thecompound of the formula (I) can be prepared by any combination of thepreparation methods or the methods that are apparent to a person skilledin the art.

Furthermore, the following abbreviations may be used in some cases inthe Examples, Preparation Examples, and Tables below.

Rf: Preparation Example No.,

Ex: Example No.,

Data: Physicochemical data,

ESI+: representing m/z values in ESI-MS (positive ions), andrepresenting [M+H]⁺ peaks unless otherwise specified,

APCI/ESI+: representing m/z values in APCI-MS (positive ions) and ESI-MS(positive ions), and representing [M+H]⁺ peaks unless otherwisespecified,

FAB+: representing m/z values in FAB-MS (positive ions), andrepresenting [M+H]⁺ peaks unless otherwise specified,

EI: representing m/z values in EI-MS (positive ions), and representing[M]peaks unless otherwise specified,

NMR-DMSO-d₆: δ (ppm) in ¹H-NMR in DMSO-d₆,

NMR-CDCl₃: δ (ppm) in ¹H-NMR in CDCl₃,

in the present specification, in the formula:

the double bond indicates that a mixture of isomers of E isomers and Zisomers exists,

Structure: Structural formula (A case where HCl, PA, or L-TA isdescribed in the structural formula means that the compound forms a saltwith the acid. Further, a case where a numeral is present before theacid means that the compound forms a salt having a valence with thatnumber, for example, 2HCl means formation of dihydrochloride).

cis: indicating that a steric structure in the structural formula is inthe cis configuration,

trans: indicating that a steric structure in the structural formula isin the trans configuration,

Syn: preparation method (in which the numeral alone shows that thecompound is prepared by the same preparation method as the compoundhaving the Example No. and R prefixed before the numeral shows that thecompound is prepared by the same preparation method as the compoundhaving the Preparation Example No.),

L-TA: L-tartaric acid,

HCl: hydrochloric acid,

PA: phosphoric acid,

Boc: tert-butoxycarbonyl group,

CDI: 1,1′-carbonyldiimidazole

DMSO: dimethylsulfoxide,

THF: tetrahydrofuran,

EtOAc: ethyl acetate,

MgSO₄: anhydrous magnesium sulfate,

DMF: N,N-dimethylformamide,

Na₂SO₄: anhydrous sodium sulfate,

MeOH: methanol,

EtOH: ethanol

CHCl₃: chloroform,

NMP: N-methyl-2-pyrrolidone,

WSC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide,

HOBt: 1-hydroxybenzotriazole,

TEA: triethylamine,

DIPEA: diisopropylethylamine,

MeCN: acetonitrile,

TFA: trifluoroacetic acid,

DME: 1,2-dimethoxyethane,

DBU: diazabicycloundecene,

TBAF: tetrabutylammonium fluoride,

BINAP: 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine),

Pd₂(dba)₃: tris(dibenzylideneacetone)dipalladium,

NaBH₄: sodium borohydride,

DIAD: diisopropyl azodicarboxylate,

DCE: 1,2-dichloroethane,

MsCl: methanesulfonyl chloride,

TBSCJ: tert-butyldimethylchlorosilane,

Boc₂O: di-tert-butyldicarbonate,

DMAP: 4-(dimethylamino)pyridine,

iPrNH₂: isopropylamine,

NaH: sodium hydride (55% suspended in oil),

NaOH: sodium hydroxide,

IPA: isopropyl alcohol,

NaHCO₃: sodium hydrogen carbonate,

CH₂Cl₂: dichloromethane,

NH₃: ammonia,

M: mol/L.

Preparation Example 12

Tetrakis(triphenylphosphine)palladium (36 mg) and sodium carbonate (330mg) were added to a mixture of4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)phenyl]morpholine (300mg),(3-bromophenyl)methanol (233 mg), DME (6 ml), and water (3 ml),followed by stirring at 80° C. overnight, and then the reaction mixturewas concentrated under reduced pressure. Water and CHCl₃ were added tothe obtained residue, and the organic layer was dried over MgSO₄, andthen concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (EtOAc/hexane/CHCl₃) toobtain [4′-(morpholin-4-yl) biphenyl-3-yl]methanol (242 mg).

Preparation Example 32

Under argon atmosphere, sodium carbonate (1000 mg) andtetrakis(triphenylphosphine)palladium (170 mg) were added to a mixtureof (2-fluoro-3-formylphenyl)boronic acid (700 mg), tert-butyl4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate(1000 mg), toluene (15 ml), EtOH (5 ml) and water (5 ml) followed bystirring at 80° C. overnight. The reaction mixture was concentratedunder reduced pressure, and CHCl₃ and a saturated aqueous sodiumhydrogen carbonate solution were then added thereto. The organic layerwas dried over Na₂SO₄ and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(hexane/EtOAc). The purified product thus obtained was mixed with EtOH,and NaBH₄ (120 mg) was added thereto, followed by stirring at roomtemperature for 30 minutes. The reaction mixture was concentrated underreduced pressure, and then EtOAc and water were added thereto. Theorganic layer was dried over Na₂SO₄ and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (hexane/EtOAc) to obtain tert-butyl4-[2-fluoro-3-(hydroxymethyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate(637 mg).

Preparation Example 33

(3-Bromophenyl)methanol (10 g) was mixed with dioxane (100 ml), and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (15 g),bis(triphenylphosphine)palladium chloride (1.2 g), and potassium acetate(15.8 g) were added thereto, followed by stirring at 80° C. for 1 day.The reaction mixture was concentrated under reduced pressure, and CHCl₃and a saturated aqueous sodium hydrogen carbonate solution were addedthereto. The organic layer was dried over Na₂SO₄ and concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (hexane/EtOAc) to obtain[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol (12.5g).

Preparation Example 38

A mixture of 4-(5-bromopyrimidin-2-yl)morpholine (2 g),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (2.5 g),bis(triphenylphosphine)palladium chloride (180 mg), potassium acetate(2.5 g), and dioxane (20 ml) was stirred at 80° C. overnight under argonatmosphere. Water and EtOAc were added to the reaction mixture, and theorganic layer was dried over MgSO₄ and concentrated under reducedpressure. The obtained residue was mixed with THF (10 ml) and water (10ml), and sodium perborate.tetrahydrate (3.5 g) was added thereto,followed by stirring at room temperature overnight. Then, a saturatedaqueous ammonium chloride solution was added thereto. The aqueous layerwas extracted with EtOAc, and the organic layer was dried over MgSO₄ andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (hexane/EtOAc) to obtain2-(morpholin-4-yl)pyrimidin-5-ol (610 mg).

Preparation Example 39

Calcium carbonate (11 g) was added to a mixture ofethyl[3-(bromomethyl)phenyl]acetate (4.56 g), dioxane (70 ml) and water(70 ml), followed by stirring at 80° C. for 6 hours. EtOAc and waterwere added to the reaction mixture, and the organic layer was dried overNa₂SO₄ and concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (hexane/EtOAc). Thepurified product thus obtained was mixed with EtOH (50 ml), and a 1Maqueous NaOH solution (35 ml) was added thereto, followed by stirring atroom temperature for 1 hour. 1M hydrochloric acid (35 ml) was added tothe reaction mixture, followed by concentration under reduced pressure.MeOH and Na₂SO₄ were added to the obtained residue, and the insolublematter was removed by filtration. The filtrate was concentrated underreduced pressure to obtain [3-(hydroxymethyl)phenyl]acetic acid (1.9 g).

Preparation Example 41

Using [(3-bromo-2-fluorobenzyl)oxy](tert-butyl)dimethylsilane (6.5 g) asa starting material and cesium carbonate as a base under the samereaction conditions as in Preparation Example 228,1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperidin-4-ylbenzoate (4.5 g) was prepared.

Preparation Example 42

Under argon atmosphere,[(3-bromo-2-fluorobenzyl)oxy](tert-butyl)dimethylsilane (2 g) and ethylpiperidine-4-carboxylate (1.6 g) were mixed with toluene (30 ml), andPd₂(dba)₃ (150 mg), BINAP (300 mg), and cesium carbonate (3.2 g) wereadded thereto, followed by stirring at 100° C. for 1 hour. The reactionmixture was cooled to room temperature, and EtOAc was added thereto,followed by filtration using Celite as a filtration adjuvant. Thefiltrate was concentrated under reduced pressure, the residue was thenmixed with THF (30 ml), and a 1M TBAF/THF solution (12 ml) was addedthereto, followed by stirring at room temperature for 1 hour. To thereaction mixture were added EtOAc and water, and the organic layer wasdried over Na₂SO₄ and concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (hexane/EtOAc)to obtain ethyl1-[2-fluoro-3-(hydroxymethyl)phenyl]piperidine-4-carboxylate (1.02 g).

Preparation Example 44

tert-Butyl [(3-ethynyl-2-fluorobenzyl)oxy]dimethylsilane (1 g) was mixedwith THF (20 ml), and a 1.65M n-butyl lithium/hexane solution (2.5 ml)was added dropwise thereto at −78° C., followed by stirring at −78° C.for 30 minutes. Benzyl chloroformate (774 mg) was added dropwise theretoat the same temperature, followed by stirring overnight while raisingthe temperature to room temperature. A saturated aqueous ammoniumchloride solution was added thereto at 0° C., followed by extractionwith CHCl₃. The organic layer was washed with water and saturated brine,and dried over Na₂SO₄, and the solvent was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (EtOAc/hexane) to obtain benzyl3-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]prop-2-ynoate(1.41 g).

Preparation Example 45

tert-Butyl{2-[(chloroacetyl)(tetrahydro-2H-pyran-4-yl)amino]ethyl}carbamate(6.86 g) was mixed with THF (70 ml), and sodium hydride (55% suspendedin oil) (1.4 g) was added thereto at 0° C., followed by stirring at roomtemperature overnight. To the reaction mixture was added a saturatedaqueous ammonium chloride solution at 0° C., followed by extraction withCHCl₃. The organic layer was washed with water and saturated brine, anddried over Na₂SO₄, and the solvent was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (EtOAc/hexane/MeOH) to obtain tert-butyl3-oxo-4-(tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate (5.25 g).

Preparation Example 48

Using({1-[(benzyloxy)carbonyl]piperidin-4-yl}methyl)(triphenyl)phosphoniumiodide (6.0 g) as a starting material and lithiumbis(trimethylsilyl)amide as a base under the same conditions as inPreparation Example 581, benzyl tert-butyl4,4′-(Z)-ethene-1,2-diyldipiperidine-1-carboxylate (2.5 g) was prepared.

Preparation Example 50

1-Benzyl-4-(tetrahydro-2H-pyran-4-ylmethoxy)pyridinium bromide (1.9 g)was mixed with MeOH (35 ml), and NaBH₄ (850 mg) was added thereto,followed by stirring at room temperature for 1 hour. Acetone (6 ml) wasadded to the reaction mixture, followed by stirring at room temperaturefor 30 minutes, and then activated carbon (1 g) was added thereto,followed by stirring at room temperature for 30 minutes and filteringusing Celite as a filtration adjuvant. The filtrate was concentratedunder reduced pressure. EtOAc and a saturated aqueous sodium hydrogencarbonate solution were added to the obtained residue, and the organiclayer was dried over Na₂SO₄ and concentrated under reduced pressure. Theobtained residue was mixed with MeOH (35 ml), and ammonium formate (3 g)and 10% palladium carbon (400 mg) were added thereto, followed bystirring at 50° C. for 4 hours and filtering using Celite, and thefiltrate was concentrated under reduced pressure. EtOAc and a saturatedaqueous sodium hydrogen carbonate solution were added to the residue,and the organic layer was dried over Na₂SO₄ and concentrated underreduced pressure. The obtained residue was purified by basic silica gelcolumn chromatography (CHCl₃/MeOH) to obtain4-(tetrahydro-2H-pyran-4-ylmethoxy)piperidine (1.01 g).

Preparation Example 54

4-(Tetrahydro-2H-pyran-4-ylmethoxy)pyridine (1.1 g) was mixed with THF(12 ml), and benzyl bromide (1.4 g) was added thereto, followed bystirring at room temperature overnight. The precipitated solid wascollected by filtration to obtain1-benzyl-4-(tetrahydro-2H-pyran-4-ylmethoxy)pyridinium bromide (1.9 g).

Preparation Example 57

2-Fluoro-3-methylbenzoic acid (4 g), THF (55 ml), and tert-butanol (55ml) were mixed, and Boc₂O (7.5 g) and DMAP (1.0 g) were added thereto atroom temperature, followed by stirring at room temperature overnight.The solvent was concentrated under reduced pressure, and EtOAc and waterwere added thereto. The organic layer was dried over Na₂SO₄, andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (hexane/EtOAc) to obtain tert-butyl2-fluoro-3-methylbenzoate (3.50 g).

Preparation Example 58

tert-Butyl 3-hydroxyazetidine-1-carboxylate (4.0 g) and pyridin-4-ol(1.8 g) were mixed with THF (50 ml), and triphenylphosphine (6.23 g) wasadded thereto. A 1.9 M DIAD/toluene solution (12.5 ml) was addeddropwise, followed by stirring at 55° C. overnight. Triphenylphosphine(5 g) and a 1.9M DIAD/toluene solution (10 ml) were added to thereaction mixture, followed by stirring at 55° C. overnight. The reactionmixture was concentrated under reduced pressure, and a liquid separationoperation was carried out by the addition of EtOAc and 0.5M hydrochloricacid. The aqueous layer was adjusted to a pH of around 10 by theaddition of a 4M aqueous NaOH solution, and extracted with CHCl₃. Theorganic layer was dried over Na₂SO₄ and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (CHCl₃/MeOH) to obtain tert-butyl3-(pyridin-4-yloxy)azetidine-1-carboxylate (4.2 g).

Preparation Example 60

1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperidin-4-ol(200 mg) and pyridin-4-ol (65 mg) were mixed with THF (3 ml), andtriphenylphosphine (250 mg) was added thereto. A 1.9M DIAD/toluenesolution (0.5 ml) was added dropwise to the reaction mixture, followedby stirring at 55° C. overnight. Then, a 1M TBAF/THF solution (1 ml) wasadded to the reaction mixture, followed by stirring at room temperaturefor 1 hour. The reaction mixture was concentrated under reducedpressure, and diethyl ether and 1M hydrochloric acid were added thereto.The organic layer was separated by a liquid separation operation, andthe aqueous layer was washed with diethyl ether twice again. The aqueouslayer was adjusted to a pH of around 10 by the addition of a 4 M aqueousNaOH solution, and extracted with CHCl₃. The organic layer was driedover Na₂SO₄ and concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (CHCl₃/MeOH) toobtain {2-fluoro-3-[4-(pyridin-4-yloxy)piperidin-1-yl]phenyl}methanol(84 mg).

Preparation Example 62

tert-Butyl 3-hydroxyazetidine-1-carboxylate (3.0 g) was mixed with THF(30 ml), and sodium hydride (55% suspended in oil) (600 mg) was addedthereto, followed by stirring at room temperature for 10 minutes. Benzylbromide (2.5 ml) was added thereto, followed by stirring at roomtemperature for 3 hours. Water and EtOAc were added to the reactionmixture, and the organic layer was dried over Na₂SO₄ and concentratedunder reduced pressure. The obtained residue was mixed with DCE (30 ml),and TFA (15 g) was added thereto, followed by stirring at roomtemperature for 3 hours. The reaction mixture was concentrated underreduced pressure and purified by basic silica gel column chromatography(CHCl₃/MeOH) to obtain 3-(benzyloxy)azetidine (2.2 g).

Preparation Example 63

tert-Butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (1.1 g),2-methylpyridin-3-ol (500 mg), potassium carbonate (1.7 g), and DMF (10ml) were mixed, followed by stirring at 100° C. for 6 hours. Thereaction mixture was concentrated under reduced pressure, and CHCl₃ anda saturated aqueous sodium hydrogen carbonate solution were then addedthereto. The organic layer was dried over Na₂SO₄ and concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (CHCl₃/MeOH). The purified product thus obtained wasmixed with DCE (10 ml), and TFA (4.5 g) was added thereto, followed bystirring at room temperature for 3 hours. The reaction mixture wasconcentrated under reduced pressure, and CHCl₃ and a 1M aqueous NaOHsolution were the added thereto, and the organic layer was dried overNa₂SO₄ and concentrated under reduced pressure to obtain2-methyl-3-(piperidin-4-yloxy)pyridine (355 mg).

Preparation Example 67

1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine(500 mg) was mixed with dioxane (15 ml), and methyl5-bromopyridine-2-carboxylate (399 mg), palladium acetate (35 mg),2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (147 mg),and potassium phosphate (981 mg) were added thereto, followed bystirring at 100° C. for 48 hours. The reaction mixture was cooled toroom temperature, and filtered by the addition of CHCl₃ and Celite, andthe filtrate was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (EtOAc/hexane)to obtain methyl5-{4-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazin-1-yl}pyridine-2-carboxylate(310 mg).

Preparation Example 69

1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-4-(pyridin-3-yl)piperidin-4-ol(908 mg) was mixed with dichloromethane (15 ml), and TEA (1.1 g), DMAP(799 mg), and MsCl (749 mg) were added thereto at 0° C., followed bystirring at room temperature overnight. Water and EtAOc were added tothe reaction mixture, and the organic layer was washed with water andsaturated brine, and dried over anhydrous sodium carbonate. The solventwas concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (EtOAc/hexane) to obtain1′-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-1′,2′,3′,6′-tetrahydro-3,4′-bipyridine(477 mg).

Preparation Example 70

Dioxane (12 ml) was added to a mixture of5-iodo-2-(3-methoxyazetidin-1-yl)pyrimidine (1.14 g), tert-butyl3-oxopiperazine-1-carboxylate (941 mg), rel-(1R,2R)—N,N′-dimethylcyclohexane-1,2-diamine (223 mg), copper iodide (149 mg), and potassiumphosphate (2.5 g), followed by stirring at 100° C. overnight. Thereaction mixture was cooled to room temperature and then filtered by theaddition of CHCl₃ and Celite, and the filtrate was concentrated. Theobtained residue was purified by basic silica gel column chromatography(EtOAc/hexane) to obtain tert-butyl4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]-3-oxopiperazine-1-carboxylate(867 mg).

Preparation Example 81

2-Fluoro-4′-(morpholin-4-yl)biphenyl-3-carboaldehyde (288 mg) was mixedwith THF (3 ml), and NaBH₄ (40 mg) was added thereto. MeOH (3 ml) wasadded to the reaction mixture dropwise, followed by stirring at roomtemperature for 30 minutes. EtOAc and 1 M hydrochloric acid were addedto the reaction mixture, and the organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (hexane/EtOAc) to obtain[2-fluoro-4′-(morpholin-4-yl)biphenyl-3-yl]methanol (259 mg).

Preparation Example 135

[3-(2-Chloropyrimidin-5-yl)phenyl]methanol (200 mg) was mixed with DMF(4 ml), and 4-methoxypiperidine hydrochloride (180 mg) and potassiumcarbonate (500 mg) were added thereto, followed by stirring at 70° C.for 5 hours. The reaction mixture was concentrated under reducedpressure, and CHCl₃ and a saturated aqueous sodium hydrogen carbonatesolution were then added thereto. The organic layer was dried overNa₂SO₄ and concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (hexane/EtOAc) to obtain{3-[2-(4-methoxypiperidin-1-yl)pyrimidin-5-yl]phenyl}methanol (249 mg).

Preparation Example 159

5-{4-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazin-1-yl}pyrimidin-2-yltrifluoromethanesulfonate(200 mg) was mixed with DMF (4 ml), and 1-acetylpiperazine (72 mg) andpotassium carbonate (300 mg) were added thereto, followed by stirring at60° C. overnight. The reaction mixture was concentrated under reducedpressure, and water and EtOAc were added to the residue. The organiclayer was washed with saturated brine, then dried over Na₂SO₄, andconcentrated under reduced pressure. The obtained residue was mixed withTHF, and a 1M TBAF/THF solution was added thereto, followed by stirringat room temperature for 3 hours. Water and EtOAc were added to thereaction mixture, and the organic layer was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (EtOAc/hexane/MeOH/CHCl₃) to obtain1-[4-(5-{4-[2-fluoro-3-(hydroxymethyl)phenyl]piperazin-1-yl}pyrimidin-2-yl)piperazin-1-yl]ethanone(133 mg).

Preparation Example 162

Ethyl 3-(2-ethoxy-2-oxoethyl)benzoate (1.41 g) was mixed with THF (20ml), and lithium borohydride (260 mg) was added thereto at 0° C.,followed by stirring at room temperature overnight. A saturated ammoniumchloride solution and EtOAc were added to the reaction mixture at 0° C.The organic layer was washed with water and saturated brine, dried overNa₂SO₄, and concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (EtOAc/hexane) toobtain ethyl 3-(2-hydroxyethyl)benzoate (824 mg).

Preparation Example 163

2,5-Dibromo-1,3-thiazole (500 mg) was mixed with morpholine (2 ml),followed by stirring at 60° C. for 5 hours. Water was added to thereaction mixture, followed by stirring for 1 hour, and the resultinginsoluble matter was collected by filtration, followed by washing withwater, to obtain 4-(5-bromo-1,3-thiazol-2-yl)morpholine (475 mg).

Preparation Example 174

CHCl₃ and a saturated aqueous sodium hydrogen carbonate solution wereadded to [3-(piperazin-1-yl)phenyl]methanol dihydrochloride (240 mg) tocarry out liquid separation. The organic layer was dried over MgSO₄ andconcentrated under reduced pressure. The obtained residue was mixed withdichloromethane (5 ml), and tetrahydro-4H-pyran-4-one (100 mg) andacetic acid (168 mg) were added thereto, followed by stirring at roomtemperature for 15 minutes. Sodium triacetoxyborohydride (576 mg) wasadded to the reaction mixture at 0° C., followed by stirring at roomtemperature for 5 hours. Water and CHCl₃ were added to the reactionmixture, and the aqueous layer was adjusted to a pH of 8 to 9 by theaddition of a saturated aqueous sodium hydrogen carbonate solution. Theorganic layer was washed with water, dried over MgSO₄, and thenconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (CHCl₃/MeOH) to obtain{3-[4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl]phenyl}methanol (45 mg).

Preparation Example 177

Ethyl1-{5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}piperidine-4-carboxylate(1.4 g) was mixed with THF (10 ml) and EtOH (15 ml), and a 1M aqueousNaOH solution (5.8 ml) was added thereto, followed by stirring at roomtemperature overnight. The insoluble matter was collected by filtration,and the filtrate was concentrated under reduced pressure. Water and 1Mhydrochloric acid (5.8 ml) were added to the obtained residue at 0° C.,followed by stirring at 0° C. for 30 minutes. The solid was collected byfiltration, washed with water, and then dried at 50° C. under reducedpressure to obtain1-{5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}piperidine-4-carboxylicacid (1.29 g).

Preparation Example 182

(3-Bromophenyl)methanol (500 mg) was mixed with DMF (10 ml), and sodiumhydride (55% suspended in oil) was added thereto at 0° C., followed bystirring for 10 minutes under ice-cooling.1-(Chloromethyl)-4-methoxybenzene (520 mg) was added to the reactionmixture, followed by stirring at room temperature for 2 hours. Water andEtOAc were added to the reaction mixture, and the organic layer wasdried over MgSO₄ and concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (CHCl₃/hexane)to obtain 1-bromo-3-{[(4-methoxybenzyl)oxy]methyl}benzene (801 mg).

Preparation Example 228

[(3-Bromo-2-fluorobenzyl)oxy](tert-butyl)dimethylsilane (300 mg) wasmixed with toluene (6 ml), and 1-(2-methylpyridin-4-yl)piperazine (200mg), Pd₂(dba)₃ (43 mg), BINAP (88 mg), and sodium tert-butoxide (135 mg)were added thereto, followed by stirring at 80° C. for 5 hours. Aftercooling to room temperature, filtration was carried out by the additionof CHCl₃ and Celite, and the filtrate was concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (EtOAc/hexane/28% aqueous ammonia/MeOH/) to obtain1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-4-(2-methylpyridin-4-yl)piperazine(259 mg).

Preparation Example 285

Under argon atmosphere,[(3-bromo-2-fluorobenzyl)oxy](tert-butyl)dimethylsilane (800 mg) and4-(azetidin-3-yloxy)pyridine (268 mg) were mixed with toluene (6 ml),and Pd₂(dba)₃ (80 mg), BINAP (160 mg), and sodium tert-butoxide (300 mg)were added thereto, followed by stirring at 90° C. for 3 hours. Thereaction mixture was cooled to room temperature, and EtOAc was addedthereto, followed by carrying out filtration using Celite as afiltration adjuvant. The filtrate was concentrated under reducedpressure, and then the residue was purified by silica gel columnchromatography (hexane/EtOAc). The purified product thus obtained wasmixed with THF (6 ml), and a 1M TBAF/THF solution (3 ml) was addedthereto, followed by stirring at room temperature for 1 hour. To thereaction mixture were added a saturated aqueous ammonium chloridesolution and CHCl₃, and the organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (hexane/EtOAc) to obtain{2-fluoro-3-[3-(pyridin-4-yloxy)azetidin-1-yl]phenyl}methanol (335 mg).

Preparation Example 290

Under argon atmosphere, 4-(5-bromopyrimidin-2-yl)morpholine (700 mg) andtert-butyl piperazine-1-carboxylate (800 mg) were mixed with toluene (10ml), and Pd₂(dba)₃ (130 mg), BINAP (260 mg), and potassium tert-butoxide(500 mg) were added thereto, followed by stirring at 90° C. overnight.The reaction mixture was cooled to room temperature, the reactionmixture was concentrated under reduced pressure, and the residue waspurified by silica gel column chromatography (hexane/EtOAc). Thepurified product thus obtained was mixed with EtOH (10 ml), and 4Mhydrogen chloride/dioxane (7 ml) was added thereto, followed by stirringat room temperature overnight. The reaction mixture was concentratedunder reduced pressure, and CHCl₃ and a saturated aqueous sodiumhydrogen carbonate solution were then added thereto. The organic layerwas dried over Na₂SO₄ and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(CHCl₃/MeOH) to obtain 4-[5-(piperazin-1-yl)pyrimidin-2-yl]morpholine(239 mg).

Preparation Example 294

1-(3-{[(4-Methoxybenzyl)oxy]methyl}phenyl)-4-(pyridin-4-yl)piperazine(308 mg) was mixed with dichloromethane (2 ml), and TFA (1 ml) was addedthereto. The reaction mixture was stirred at room temperature for 1hour, and then the reaction mixture was concentrated under reducedpressure. To the obtained residue were added a saturated aqueous sodiumhydrogen carbonate solution and CHCl₃, and the organic layer was driedover MgSO₄ and concentrated under reduced pressure. The obtained residuewas purified by basic silica gel column chromatography to obtain{3-[4-(pyridin-4-yl)piperazin-1-yl]phenyl}methanol (167 mg).

Preparation Example 297

(3-Bromophenyl)methanol (5.0 g) was mixed with THF (60 ml), and TBSC1(5.0 g) and imidazole (3 g) were added thereto, followed by stirring atroom temperature overnight. The reaction mixture was concentrated underreduced pressure, and water and EtOAc were added thereto. The organiclayer was dried over Na₂SO₄ and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography toobtain [(3-bromobenzyl)oxy](tert-butyl)dimethylsilane (8.0 g).

Preparation Example 301

[(3-Bromobenzyl)oxy](tert-butyl)dimethylsilane (860 mg) was mixed withTHF (10 ml), followed by cooling to −78° C. under argon atmosphere. A1.60M n-butyl lithium/hexane solution (1.8 ml) was added dropwisethereto, followed by stirring at −78° C. for 10 minutes, and then2-morpholin-4-ylpyrimidine-5-carboaldehyde (500 mg) was added thereto.The mixture was warmed to 0° C. over 1 hour and then stirred again at 0°C. for 1 hour. Water and EtOAc were added to the reaction mixture, andthe organic layer was dried over Na₂SO₄ and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (hexane/EtOAc) to obtain[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl][2-(morpholin-4-yl)pyrimidin-5-yl]methanol(914 mg).

Preparation Example 302

[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)phenyl][2-(morpholin-4-yl)pyrimidin-5-yl]methanol(400 mg), triethylsilane (364 mg), and TFA (4 ml) were mixed, followedby stirring at room temperature overnight. The reaction mixture wasconcentrated under reduced pressure, and EtOAc and water were added tothe obtained residue. The organic layer was dried over MgSO₄ andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to obtain(3-{[2-(morpholin-4-yl)pyrimidin-5-yl]methyl}phenyl)methanol (39 mg).

Preparation Example 304

1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine(355 mg) was mixed with IPA (4.5 ml), and 4-chloro-pyrimidinehydrochloride (150 mg) and TEA (302 mg) were added thereto, followed bystirring at 60° C. overnight. The reaction mixture was cooled to roomtemperature and then concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (MeOH/CHCl₃) toobtain4-{4-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazin-1-yl}pyrimidine (391 mg).

Preparation Example 305

Ethyl 2-fluoro-3-({[2-(morpholin-4-yl)pyrimidin-5-yl]oxy}methyl)benzoate(375 mg) was mixed with toluene (5 ml), followed by cooling to 0° C. A1.01 M diisobutylaluminum hydride/toluene solution (3 ml) was addeddropwise thereto, followed by stirring at the same temperature for 1hour. The reaction mixture was subjected to liquid separation by theaddition of a 1 M aqueous NaOH solution and toluene. The organic layerwas dried over Na₂SO₄ and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(hexane/EtOAc) to obtain[2-fluoro-3-({[2-(morpholin-4-yl)pyrimidin-5-yl]oxy}methyl)phenyl]methanol(282 mg).

Preparation Example 306

1-(6-Chloropyridazine-3-yl)azetidin-3-ol (599 mg) was mixed with DMF (6ml), and sodium hydride (55% suspended in oil) (211 mg) was addedthereto at 0° C., followed by stirring at 0° C. for 10 minutes. Then,methyl iodide (916 mg) was added thereto at 0° C., followed by stirringat room temperature overnight. To the reaction mixture were added water,EtOAc, and CHCl₃, and the organic layer was washed with water andsaturated brine, then dried over anhydrous Na₂CO₃, and concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (EtOAc/hexane) to obtain3-chloro-6-(3-methoxyazetidin-1-yl)pyridazine (323 mg).

Preparation Example 307

tert-Butyl 4-hydroxypiperidine-1-carboxylate (1.0 g) was mixed with DMF(15 ml), and sodium hydride (55% suspended in oil) (300 mg) was addedthereto, followed by stirring at room temperature for 10 minutes. To thereaction mixture was added 1-bromo-3-methoxypropane (1.0 g), followed bystirring at room temperature overnight. Water was added to the reactionmixture, and the reaction mixture was concentrated under reducedpressure. EtOAc and water were added to the obtained residue, and theorganic layer was dried over Na₂SO₄ and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (hexane/EtOAc). The purified product thus obtained wasmixed with EtOH (10 ml), and a 4M hydrogen chloride/dioxane (10 ml) wasadded thereto, followed by stirring at room temperature overnight. Thereaction mixture was concentrated under reduced pressure to obtain4-(3-methoxypropoxy)piperidine hydrochloride (302 mg).

Preparation Example 309

2-Fluoro-3-methylbenzoic acid (8.0 g) was mixed with EtOH (100 ml), andconcentrated sulfuric acid was added thereto, followed by stirring at90° C. overnight. The reaction mixture was concentrated under reducedpressure, and EtOAc and water were then added thereto. The organic layerwas washed with a saturated aqueous sodium hydrogen carbonate solution,then dried over Na₂SO₄, and concentrated under reduced pressure toobtain ethyl 2-fluoro-3-methylbenzoate (7.84 g).

Preparation Example 336

1-[2-Fluoro-3-(hydroxymethyl)phenyl]piperidine-4-carboxylic acid (100mg) and morpholine (50 mg) were mixed with DCE (3 ml), and WSChydrochloride (140 mg) and HOBt (95 mg) were added thereto, followed bystirring at room temperature for 3 hours. A saturated aqueous sodiumhydrogen carbonate solution and CHCl₃ were added to the reactionmixture, and the organic layer was dried over Na₂SO₄ and concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (CHCl₃/MeOH) to obtain{1-[2-fluoro-3-(hydroxymethyl)phenyl]piperidin-4-yl}(morpholin-4-yl)methanone(126 mg).

Preparation Example 341

(2-Fluoro-3-{4-[2-(piperidin-4-yl)ethyl]piperidin-1-yl}phenyl)methanol(200 mg) and acetic acid (63 mg) were mixed with DCE (3 ml), and WSChydrochloride (220 mg) and HOBt (155 mg) were added thereto, followed bystirring at room temperature for 3 hours. A saturated aqueous sodiumhydrogen carbonate solution and CHCl₃ were added to the reactionmixture, and the organic layer was liquid separation and concentratedunder reduced pressure. The obtained residue was mixed with MeOH (3 ml),and a 1M aqueous NaOH solution (1 ml) was added thereto, followed bystirring at room temperature for 30 minutes. The reaction mixture wasconcentrated under reduced pressure, and CHCl₃ and a saturated aqueoussodium hydrogen carbonate solution were then added thereto. The organiclayer was dried over Na₂SO₄ and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(CHCl₃/MeOH) to obtain1-[4-(2-{1-[2-fluoro-3-(hydroxymethyl)phenyl]piperidin-4-yl}ethyl)piperidin-1-yl]ethanone (211 mg).

Preparation Example 343

5-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-(piperidin-4-yloxy)pyrimidine (150 mg) and cyclohexane carboxylic acid (82 mg) were mixedwith DCE (3.6 ml), and WSC hydrochloride (125 mg) and HOBt (85 mg) wereadded thereto, followed by stirring at room temperature for 3 hours. Asaturated aqueous sodium hydrogen carbonate solution and CHCl₃ wereadded to the reaction mixture, and the organic layer was dried overNa₂SO₄ and concentrated under reduced pressure. The obtained residue wasmixed with THF (3.6 ml), and a 1M TBAF/THF solution (0.85 ml) was addedthereto, followed by stirring at room temperature for 1 hour. EtOAc andan aqueous ammonium chloride solution were added to the reactionmixture, and the organic layer was dried over Na₂SO₄ and concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (CHCl₃/MeOH) to obtain cyclohexyl[4-({5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}oxy)piperidin-1-yl]methanone(148 mg).

Preparation Example 347

1-(3-Bromophenyl)methanamine (10 g) was mixed with THF (100 ml), andBoc₂O (12.9 g) was added thereto, followed by stirring at roomtemperature overnight. The reaction mixture was concentrated underreduced pressure and the residue was purified by silica gel columnchromatography (EtOAc/hexane) to obtain tert-butyl(3-bromobenzyl)carbamate (15.0 g).

Preparation Example 376

1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-3-methoxyazetidine(121 mg) was mixed with THF (4 ml), and a 1M TBAF/THF solution (0.8 ml)was added thereto, followed by stirring at room temperature for 1 hour.Water and EtOAc were added to the reaction mixture, and the organiclayer was dried over Na₂SO₄ and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography toobtain [2-fluoro-3-(3-methoxyazetidin-1-yl)phenyl]methanol (72 mg).

Preparation Example 478

tert-Butyl 4-[2-(morpholin-4-yl)pyrimidin-5-yl]piperazine-1-carboxylate(1.42 g) was mixed with MeOH (20 ml) and THF (20 ml), and a 4M hydrogenchloride/EtOAc (10 ml) was added thereto, followed by stirring at roomtemperature overnight and then stirring for 30 minutes underice-cooling. The precipitated solid was collected by filtration andwashed with EtOAc to obtain4-[5-(piperazin-1-yl)pyrimidin-2-yl]morpholine dihydrochloride (1.15 g).

Preparation Example 508

tert-Butyl 4-[2-fluoro-3-(hydroxymethyl)phenyl]piperidine-1-carboxylate(352 mg) was mixed with EtOH (5 ml), and 4M hydrogen chloride/dioxane (3ml) was added thereto, followed by stirring at room temperatureovernight. The reaction mixture was concentrated under reduced pressure,and then EtOH and potassium carbonate were added thereto, followed bystirring at 60° C. for 5 hours. The reaction mixture was filtered andthe filtrate was concentrated under reduced pressure. The reactionmixture was mixed with THF (5 ml), and TBSC1 (450 mg) and imidazole (210mg) were added thereto, followed by stirring at room temperature for 1hour. EtOAc and water were added to the reaction mixture, and theorganic layer was dried over Na₂SO₄ and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (CHCl₃/MeOH) to obtain4-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperidine(271 mg).

Preparation Example 514

tert-Butyl4-{5-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]pyrimidin-2-yl}piperidine-1-carboxylate (170 mg) was mixed with MeOH (1.7 ml), and a 4M hydrogenchloride/EtOAc (0.17 ml) was added thereto, followed by stirring at roomtemperature overnight. The reaction mixture was concentrated underreduced pressure, and 10% MeOH/CHCl₃ and a saturated aqueous sodiumhydrogen carbonate solution were added to the residue. Then, thereaction mixture was concentrated under reduced pressure. 10% MeOH/CHCl₃was added to the obtained residue, followed by stirring for 30 minutes.The filtrate was concentrated under reduced pressure to obtain{2-fluoro-3-[2-(piperidin-4-yl)pyrimidin-5-yl]phenyl}methanol (96 mg).

Preparation Example 516

Methyl 3-(bromomethyl)benzoate (4.0 g) was mixed with toluene (40 ml),and triphenylphosphine (5.0 g) was added thereto, followed by stirringat 90° C. overnight. The precipitated solid was collected by filtrationto obtain [3-(methoxycarbonyl)benzyl](triphenyl)phosphonium bromide (8.2g).

Preparation Example 518

1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)phenyl]-4-(pyridin-2-yl)piperazine(240 mg) was mixed with THF (2 ml), and a 1M hydrochloric acid (2 ml)was added thereto, followed by stirring at room temperature for 5 hours.A saturated aqueous sodium hydrogen carbonate solution and CHCl₃ wereadded to the reaction mixture, and the organic layer was dried overMgSO₄ and concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (hexane/EtOAc) to obtain{3-[4-(pyridin-2-yl)piperazin-1-yl]phenyl}methanol (166 mg).

Preparation Example 548

Benzyl 3-oxo-4-(pyridin-3-ylmethyl)piperazine-1-carboxylate (345 mg) wasmixed with EtOH (7 ml), and 10% palladium carbon (70 mg) was addedthereto under argon atmosphere to change the atmosphere to hydrogenatmosphere, followed by stirring at room temperature overnight. Thereaction mixture was filtered using Celite as a filtration adjuvant, andthe filtrate was concentrated under reduced pressure to obtain1-(pyridin-3-ylmethyl)piperazin-2-one (190 mg).

Preparation Example 563

tert-Butyl 4-hydroxypiperidine-1-carboxylate (2.0 g) was mixed with THF(20 ml), and TEA (3 ml) and benzoyl chloride (1.2 g) were added thereto,followed by stirring at room temperature for 1 hour. Water and EtOAcwere added to the reaction mixture, and the organic layer was dried overNa₂SO₄ and concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (hexane/EtOAc) to obtaintert-butyl 4-(benzoyloxy)piperidine-1-carboxylate (2.45 g).

Preparation Example 564

tert-Butyl 4-hydroxypiperidine-1-carboxylate (3.0 g) was mixed with DCE(30 ml), and TEA (3.0 ml) and benzoyl chloride (2.4 g) was addedthereto, followed by stirring at room temperature for 1 hour. Asaturated aqueous sodium hydrogen carbonate solution and EtOAc wereadded to the reaction mixture, and the organic layer was dried overNa₂SO₄ and concentrated under reduced pressure. The obtained residue wasmixed with DCE (30 ml), and TFA (10 ml) was added thereto, followed bystirring at room temperature for 5 hours. The reaction mixture wasconcentrated under reduced pressure, and then the residue was purifiedby basic silica gel column chromatography (CHCl₃/MeOH) to obtainpiperidin-4-yl benzoate (3.1 g).

Preparation Example 568

Under argon atmosphere, ethynyl(trimethyl)silane (9.0 ml) was mixed withtriethylamine (50 ml), and (3-bromo-2-fluorophenyl)methanol,bis(triphenylphosphine)palladium chloride (II) (1.54 g), and copperiodide (420 mg) were added thereto, followed by stirring at 90° C.overnight. The reaction mixture was cooled to room temperature, andEtOAc was added thereto, followed by filtering using Celite as afiltration adjuvant. The filtrate was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography (hexane/EtOAc) to obtain{2-fluoro-3-[(trimethylsilyl)ethynyl]phenyl}methanol (4.88 g).

Preparation Example 572

tert-Butyl({2-fluoro-3-[(trimethylsilyl)ethynyl]benzyl}oxy)dimethylsilane(4.13 g) was mixed with EtOH (61 ml), and potassium carbonate (847 mg)was added thereto, followed by stirring at room temperature for 1 hour.Water and CHCl₃ were added to the reaction mixture at 0° C., and theorganic layer was washed with water and saturated brine, dried overNa₂SO₄, and concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (EtOAc/hexane) toobtain tert-butyl[(3-ethynyl-2-fluorobenzyl)oxy]dimethylsilane (3.19 g).

Preparation Example 573

H₂SO₄ (44 g) was added to water (18 ml) at 0° C., and(3-cyanophenyl)acetic acid (1.5 g) was added thereto at 0° C., followedby stirring at 100° C. overnight, then warming to 130° C., and stirringfor 5 hours. The reaction mixture was cooled to room temperature, andEtOH (190 ml) was then added thereto, followed by stirring at 90° C. for2 days. The reaction mixture was concentrated under reduced pressure,and EtOAc and water were added to the residue. Then, the organic layerwas washed with water, a saturated aqueous sodium hydrogen carbonatesolution, and saturated brine, dried over Na₂SO₄, and then concentratedunder reduced pressure to obtain ethyl 3-(2-ethoxy-2-oxoethyl)benzoate(1.41 g).

Preparation Example 574

Ethyl 3-(2-hydroxyethyl)benzoate (824 mg) was mixed with dichloromethane(10 ml), DIPEA (1.5 ml) was added thereto, and methanesulfonyl chloride(972 mg) was added dropwise thereto at 0° C., followed by stirring for1.5 hours while slowly warming to room temperature. Water was added tothe reaction mixture, followed by stirring for 10 minutes, and then theorganic layer was washed with water and saturated brine, dried overNa₂SO₄, and then concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (EtOAc/hexane) to obtainethyl 3-{2-[(methylsulfonyl)oxy]ethyl}benzoate (1.12 g).

Preparation Example 581

[3-(Methoxycarbonyl)benzyl](triphenyl)phosphonium bromide (930 mg) wasmixed with DMF (6 ml), and potassium tert-butoxide (300 mg) was addedthereto at 0° C., followed by stirring for 30 minutes.2-(Morpholin-4-yl)pyrimidine-5-carboaldehyde (300 mg) was added to thereaction mixture, followed by stirring at 0° C. for 1 hour, and stirringagain at room temperature for 1 hour. The reaction mixture wasconcentrated under reduced pressure, and EtOAc and a saturated aqueoussodium hydrogen carbonate solution were then added thereto. The organiclayer was dried over Na₂SO₄ and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(hexane/EtOAc) to obtain methyl3-{2-[2-(morpholin-4-yl)pyrimidin-5-yl]vinyl}benzoate (377 mg).

Preparation Example 582

Ethyl 3-{2-[(methylsulfonyl)oxy]ethyl}benzoate (170 mg) was mixed withMeCN (3.4 ml), and 1,2,3,4,5,6-hexahydro-[4,4′]bipyridinyl (122 mg) andpotassium carbonate (173 mg) were added thereto, followed by stirring at60° C. overnight. After cooling to room temperature, the insolublematter was removed by filtration and the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (MeOH/CHCl₃) to obtain ethyl3-{2-[4-(pyridin-4-yl)piperidin-1-yl]ethyl}benzoate (121 mg).

Preparation Example 584

Ethyl 3-{2-[4-morpholin-4-yl)piperidin-1-yl]ethyl}benzoate (337 mg) wasmixed with THF (7 ml), and aluminum lithium hydride (74 mg) was addedthereto at 0° C., followed by stirring at 0° C. for 1 hour. Sodiumsulfate decahydrate was added to the reaction mixture at 0° C., followedby stirring at room temperature overnight, the insoluble matter wasremoved by filtration, and the filtrate was concentrated under reducedpressure to obtain(3-{2-[4-(morpholin-4-yl)piperidin-1-yl]ethyl}phenyl)methanol (281 mg).

Preparation Example 589

Ethyl (3-methylphenyl)acetate (5.36 g) was mixed with carbontetrachloride (80 ml), followed by heating at 90° C. N-Bromosuccinimide(5.62 g) and α,α′-azobisisobutyronitrile (250 mg) were added thereto,followed by stirring at 90° C. for 5 hours. The reaction mixture wascooled to room temperature, and then the solid was removed byfiltration. The filtrate was concentrated under reduced pressure, andthe residue was purified by silica gel column chromatography(hexane/EtOAc) to obtain ethyl [3-(bromomethyl)phenyl]acetate (4.56 g).

Preparation Example 592

2-Fluoro-3-formylphenyl)boronic acid (5.14 g) was mixed with THF (51 ml)and water (51 ml), and sodium perborate.trihydrate (17 g) was addedthereto, followed by stirring at room temperature overnight. EtOAc and1M hydrochloric acid were added to the reaction mixture, and the organiclayer was dried over Na₂SO₄ and concentrated under reduced pressure. Theobtained residue was mixed with EtOH (50 ml), and NaBH₄ (1.4 g) wasadded thereto, followed by stirring at room temperature for 1 hour. Thereaction mixture was concentrated under reduced pressure, and EtOAc and1M hydrochloric acid were then added thereto. The organic layer wasdried over Na₂SO₄ and concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (hexane/EtOAc)to obtain 2-fluoro-3-(hydroxymethyl)phenol (2.2 g).

Preparation Example 593

2-(Morpholin-4-yl)pyrimidin-5-ol (300 mg) and ethyl3-(bromomethyl)-2-fluorobenzoate (850 mg) were mixed with MeCN (5 ml),THF (2 ml) and DMF (1 ml), and potassium carbonate was added thereto,followed by stirring at room temperature for 1 hour. The reactionmixture was concentrated under reduced pressure, and EtOAc and waterwere then added thereto. The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (hexane/EtOAc) to obtain ethyl2-fluoro-3-({[2-(morpholin-4-yl)pyrimidin-5-yl]oxy}methyl)benzoate (378mg).

Preparation Example 594

5-Bromo-2-chloropyridine (5.0 g) was mixed with N,N-dimethylacetamide(25 ml), and morpholine (23 ml) was added thereto, followed by stirringat 130° C. for 2 days. The reaction mixture was concentrated underreduced pressure, and water was added to the residue, followed byextraction with EtOAc, and the organic layer was washed with saturatedbrine and dried over Na₂SO₄. The organic layer was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (hexane/EtOAc) to obtain4-(5-bromopyridin-2-yl)morpholine (6.07 g).

Preparation Example 596

5-Bromo-2-fluoropyridine (1.7 g) was mixed with N,N-dimethylacetamide (5ml), and 3-methoxyazetidine hydrochloride (335 mg) and potassiumcarbonate (1.5 g) were added thereto, followed by stirring at 100° C.overnight. The reaction mixture was concentrated under reduced pressure,and CHCl₃ and water were then added thereto. The organic layer was driedover Na₂SO₄ and concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (hexane/EtOAc)to obtain 5-bromo-2-(3-methoxyazetidin-1-yl)pyridine (581 mg).

Preparation Example 603

1′-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-1′,2′,3′,6′-tetrahydro-3,4′-bipyridine(257 mg) was mixed with EtOH (5 ml), and 10% palladium carbon (55 mg)was added thereto under argon atmosphere, followed by stirring at roomtemperature overnight under hydrogen atmosphere. The reaction mixturewas filtered using Celite as a filtration adjuvant, and the filtrate wasconcentrated under reduced pressure to obtain3-{1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperidin-4-yl}pyridine(239 mg).

Preparation Example 613

tert-Butyl4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]-3,6-dihydropyridine-1(2H)-carboxylate(483 mg) was mixed with EtOH (5 ml), and 10% palladium carbon (100 mg)was added thereto, followed by stirring at room temperature for 5 hoursunder hydrogen atmosphere. The reaction mixture was filtered usingCelite as a filtration adjuvant, and the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane/EtOAc). The purified product thus obtained wasmixed with EtOH (5 ml), and 4M hydrogen chloride/dioxane (3.5 ml) wasadded thereto, followed by stirring at room temperature overnight. Thereaction mixture was concentrated under reduced pressure, and then mixedwith EtOH (5 ml), and potassium carbonate (2.0 g) was added thereto,followed by stirring at 80° C. for 2 hours. The reaction mixture wasfiltered and the filtrate was concentrated under reduced pressure toobtain 2-(3-methoxyazetidin-1-yl)-5-(piperidin-4-yl)pyrimidine (143 mg).

Preparation Example 614

4-(4-Methylpyrimidin-2-yl)morpholine (300 mg) was mixed withdichloromethane (4 ml), and N-bromosuccinimide (357 mg) was addedthereto at 0° C., followed by stirring at room temperature for 1 hour.Hexane was added to the reaction mixture, followed by purification bysilica gel column chromatography (EtOAc/hexane), to obtain4-(5-bromo-4-methylpyrimidin-2-yl) morpholine (372 mg).

Preparation Example 617

{2-Fluoro-3-[2-(morpholin-4-yl)pyrimidin-5-yl]phenyl}methanol (337 mg),1H-isoindole-1,3(2H)-dione (257 mg) and triphenylphosphine (458 mg) weremixed with THF, and diethyl azodicarboxylate (40% toluene solution)(0.68 ml) was added thereto at 0° C., followed by stirring at roomtemperature overnight. The reaction mixture was stirred at 0° C. for 30minutes, then filtered, washed with ice-cooled THF, and dried at 50° C.under reduced pressure to obtain2-{2-fluoro-3-[2-(morpholin-4-yl)pyrimidin-5-yl]benzyl}-1H-isoindole-1,3(2H)-dione(452 mg).

Preparation Example 631

4-(5-Bromo-4-methylpyrimidin-2-yl)morpholine (372 mg),(2-fluoro-3-formylphenyl)boronic acid (315 mg), and potassium phosphate(918 mg) were mixed with toluene (10 ml) and water (10 ml), andpalladium acetate (16 mg) anddicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (59 mg) were addedthereto, followed by stirring at 100° C. for 4 hours.(2-Fluoro-3-formylphenyl)boronic acid (315 mg), potassium phosphate (918mg), palladium acetate (16 mg),dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (59 mg), and water(1 ml) were added to the reaction mixture, followed by stirring at 100°C. overnight. The reaction mixture was cooled to room temperature, CHCl₃and water were then added thereto, and the insoluble matter was removedby filtration. The organic layer of the filtrate was washed with waterand saturated brine, dried over Na₂SO₄, and then concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (EtOAc/hexane/CHCl₃) to obtain2-fluoro-3-[4-methyl-2-(morpholin-4-yl)pyrimidin-5-yl]benzaldehyde (282mg).

Preparation Example 638

Tetrahydro-2H-pyran-4-ol (200 mg) was mixed with THF (5 ml), and sodiumhydride (55% suspended in oil) (120 mg) was added thereto, followed bystirring at room temperature for 5 minutes. 5-Bromo-2-chloropyrimidine(460 mg) was added to the reaction mixture, followed by stirring at roomtemperature. Water and EtOAc were added to the reaction mixture, and theorganic layer was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (hexane/EtOAc)to obtain 5-bromo-2-(tetrahydro-2H-pyran-4-yloxy)pyrimidine (361 mg).

Preparation Example 651

1-[4-(Hydroxymethyl)piperidin-1-yl]ethan-1-one (200 mg) and THF (4 ml)were mixed, and NaH (70 mg) was added thereto, followed by stirring atroom temperature for 10 minutes.5-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-chloropyrimidine(200 mg) was added to the reaction mixture, followed by stirring at roomtemperature for 1 hour, and then 1M TBAF/THF (1.2 ml) was added thereto,followed by stirring at room temperature. Water and EtOAc were added tothe reaction mixture, and the organic layer was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (hexane/EtOAc/CHCl₃/MeOH) to obtain1-{4-[({5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}oxy)methyl]piperidin-1-yl}ethan-1-one (167 mg).

Preparation Example 653

5-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-chloropyrimidine(200 mg) was mixed with THF (4 ml), and sodium ethoxide (132 mg) wasadded thereto, followed by stirring at room temperature for 3 hours, andthen a 1M TBAF/THF solution (1.2 ml) was added thereto, followed bystirring at room temperature for 1 hour. Water and EtOAc were added tothe reaction mixture, and the organic layer was concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (hexane/EtOAc) to obtain[3-(2-ethoxypyrimidin-5-yl)-2-fluorophenyl]methanol (129 mg).

Preparation Example 663

Methyl 3-{[(tert-butoxycarbonyl)amino]methyl}benzoate (4.6 g) was mixedwith toluene (50 ml), followed by cooling to 0° C. Sodiumbis(2-methoxyethoxy)aluminum hydride (65% toluene solution) (20 g) wasadded dropwise over 30 minutes, followed by stirring at 0° C. for 1hour. A 1M aqueous NaOH solution (30 ml) was added dropwise to thereaction mixture, and CHCl₃ was then added thereto. The organic layerwas dried over Na₂SO₄ and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(hexane/EtOAc) to obtain tert-butyl [3-(hydroxymethyl)benzyl]carbamate(4.1 g).

Preparation Example 671

4,4′-Bipiperidine dihydrochloride (2.95 g) was mixed with MeOH (25 ml),and a mixture of benzyl chloroformate (2.2 g) and toluene (5 ml) wasadded dropwise thereto over 1 hour while keeping the solution neutral byadding a 6M aqueous NaOH solution at the same time. The reaction mixturewas stirred at room temperature for 30 minutes and then concentratedunder reduced pressure. CHCl₃, and a saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The organic layerwas dried over Na₂SO₄ and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(CHCl₃/MeOH) to obtain benzyl 4,4′-bipiperidine-1-carboxylate (1.5 g).

Preparation Example 674

tert-Butyl 3-(piperidin-4-yloxy)azetidine-1-carboxylate (2.78 g) wasmixed with THF (40 ml), and TEA (3.5 ml) and benzyl chloroformate (2.7g) were added thereto, followed by stirring at room temperature for 3hours. EtOAc and water were added to the reaction mixture, and theorganic layer was dried over Na₂SO₄ and concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (hexane/EtOAc).

The purified product thus obtained was mixed with EtOH (40 ml), and a 4Mhydrogen chloride/dioxane solution (30 ml) was added thereto, followedby stirring at room temperature overnight. The reaction mixture wasconcentrated under reduced pressure, and CHCl₃ and a 1M aqueous NaOHsolution were then added thereto. The organic layer was dried overNa₂SO₄ and then concentrated under reduced pressure to obtain benzyl4-(azetidin-3-yloxy)piperidine-1-carboxylate (1.97 g).

Preparation Example 677

2-(Hydroxymethyl)pyrrolidine (500 mg) was mixed with dichloromethane (5ml), and TEA (0.9 ml) and acetyl chloride (407 mg) were added thereto at0° C., followed by stirring at room temperature overnight. 8M Potassiumhydroxide was added to the reaction mixture, followed by stirring atroom temperature for 1 hour. The reaction mixture was extracted by theaddition of water and CHCl₃/MeOH (4:1), the organic layer was washedwith water and saturated brine, and dried over anhydrous Na₂SO₄, and thesolvent was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (MeOH/CHCl₃) to obtain1-[2-(hydroxymethyl)pyrrolidin-1-yl]ethanone (442 mg).

Preparation Example 680

{2-Fluoro-3-[2-(piperidin-4-yl)pyrimidin-5-yl]phenyl}methanol (80 mg)was mixed with dichloromethane (1.6 ml), and TEA (85 mg) and acetylchloride (48 mg) were added thereto at 0° C. The reaction mixture wasconcentrated under reduced pressure, the residue was mixed with MeOH,and a 1M aqueous NaOH solution (0.8 ml) was added thereto, followed bystirring for 3 hours. 1M hydrochloric acid was added to the reactionmixture, and CHCl₃/water was added to the reaction liquid. The aqueouslayer was extracted with CHCl₃, and the prepared organic layer was driedover Na₂SO₄ and then concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (CHCl₃/MeOH) toobtain1-(4-{5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}piperidin-1-yl)ethanone(90 mg).

Preparation Example 686

1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-4,4′-bipiperidine(125 mg) and TEA (0.15 ml) were mixed with DCE (3 ml), and acetylchloride (39 mg) was added thereto, followed by stirring at roomtemperature for 1 hour. A saturated aqueous sodium hydrogen carbonatesolution and CHCl₃ were added to the reaction mixture, and the organiclayer was dried over Na₂SO₄ and concentrated under reduced pressure. Theobtained residue was mixed with THF (3 ml), and a 1M TBAF/THF solution(0.6 ml) was added thereto, followed by stirring at room temperature for1 hour. To the reaction mixture were added an aqueous ammonium chloridesolution and EtOAc, the organic layer was dried over Na₂SO₄, and thesolvent was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (hexane/EtOAc) toobtain1-{1′-[2-fluoro-3-(hydroxymethyl)phenyl]-4,4′-bipiperidin-1-yl}ethanone(84 mg).

Preparation Example 707

[3-(2-Chloropyrimidin-5-yl)-2-fluorophenyl]methanol (600 mg) was mixedwith DMF (12 ml), and piperazine (2.2 g) was added thereto, followed bystirring at room temperature overnight. The reaction mixture wasconcentrated under reduced pressure, and water was added to the residue,followed by stirring at 0° C. for 1 hour. The produced solid wascollected by filtration, washed with water, and then dried at 50° C.under reduced pressure to obtain{2-fluoro-3-[2-(piperazin-1-yl)pyrimidin-5-yl]phenyl}methanol (697 mg).

Preparation Example 709

5-{4-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazin-1-yl}pyrimidin-2-yltrifluoromethanesulfonate (200 mg) was mixed with THF (4 ml), and2-methoxyethanamine (864 mg) was added thereto, followed by stirring at60° C. overnight. Water and EtOAc were added to the reaction mixture,and the organic layer was concentrated under reduced pressure. Theobtained residue was mixed with THF (5 ml), and a 1M TBAF/THF solution(1.6 ml) was added thereto, followed by stirring at room temperatureovernight. Water and EtOAc were added to the reaction mixture, and theorganic layer was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (EtOAc/hexane)to obtain[2-fluoro-3-(4-{2-[(2-methoxyethyl)amino]pyrimidin-5-yl}piperazin-1-yl)phenyl]methanol(105 mg).

Preparation Example 712

tert-Butyl 3-(pyridin-4-yloxy)azetidine-1-carboxylate (494 mg) was mixedwith DCE (5 ml), and TFA (2 ml) was added thereto, followed by stirringat room temperature for 5 hours. The reaction mixture was concentratedunder reduced pressure, and the obtained residue was purified by basicsilica gel column chromatography (CHCl₃/MeOH) to obtain4-(azetidin-3-yloxy)pyridine (268 mg).

Preparation Example 749

Using 2-(3-methoxyazetidin-1-yl)pyrazine (451 mg) as a starting materialand N-chlorosuccinimide as a halogenating agent under the same reactionconditions as in Preparation Example 614,2-chloro-5-(3-methoxyazetidin-1-yl)pyrazine (303 mg) was prepared.

Preparation Example 752

1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine(400 mg) was suspended in toluene (8 ml), and 3-chloropyridazinehydrochloride (242 mg), Pd₂(dba)₃(56 mg),dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (51 mg), and sodiumtert-butoxide (308 mg) were added thereto, followed by stirring at 100°C. overnight. The reaction mixture was cooled to room temperature, andfiltered by the addition of CHCl₃ and Celite, and the filtrate wasconcentrated. The obtained residue was purified by silica gel columnchromatography (EtOAc:hexane=70:30 to 100:0), and then purified by basicsilica gel column chromatography (EtOAc/hexane) to obtain3-{4-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazin-1-yl}pyridazine(325 mg).

Preparation Example 754

3-Methoxyazetidine hydrochloride (100 mg) was mixed with THF (3 ml), andchloroacetic acid anhydride (166 mg) and sodium hydrogen carbonate (272mg) were added thereto, followed by stirring at room temperatureovernight. Water and sodium chloride were added to the reaction mixture,followed by stirring for 30 minutes. Then, after extraction with EtOActwice, the organic layer was washed with saturated brine and dried overNa₂SO₄, and the organic layer was concentrated under reduced pressure toobtain 2-chloro-1-(3-methoxyazetidin-1-yl)ethanone (130 mg).

Preparation Example 758

A mixture of1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazineand MeCN was added to 2-chloro-1-(3-methoxyazetidin-1-yl)ethanone (130mg) and potassium carbonate (219 mg), followed by stirring at 80° C. for3 hours. CHCl₃ was added to the reaction mixture, and the insolublematter was removed by filtration. The filtrate was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography (MeOH/CHCl₃) to obtain2-{4-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazin-1-yl}-1-(3-methoxyazetidin-1-yl)ethanone (354 mg).

Preparation Example 760

5-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-[4-(vinylsulfonyl)piperazin-1-yl]pyrimidine(360 mg) was mixed with THF (3 ml) and MeOH (4 ml), and a 1M aqueousNaOH solution (1.46 ml) was added thereto, followed by stirring at roomtemperature for 3 hours. CHCl₃ was added to the reaction mixture, whichwas washed with water and saturated brine, and dried over Na₂SO₄. Then,the organic layer was concentrated under reduced pressure to obtain5-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-{4-[(2-methoxyethyl)sulfonyl]piperazin-1-yl}pyrimidine(353 mg).

Preparation Example 761

1-Acetylpiperidine-4-carboxylic acid (161 mg) was mixed withdichloromethane (5 ml), and oxalyl chloride (124 mg) and DMF (3 mg) wereadded thereto, followed by stirring at room temperature for 1 hour. TEAand 3-(2-aminopyrimidin-5-yl)-2-fluorobenzaldehyde (170 mg) were addedthereto at 0° C., followed by stirring at room temperature overnight. Amixture of 1-acetylpiperidine-4-carboxylic acid (161 mg), oxalylchloride (0.084 ml), and DMF in dichloromethane (3 ml), which is mixedin advance and was stirred for 1 hour, was added thereto at 0° C.,followed by stirring at room temperature for 3 hours. Furthermore, amixture of 1-acetylpiperidine-4-carboxylic acid (161 mg), oxalylchloride (0.084 ml), and DMF in dichloromethane (3 ml), after mixingwith the reaction mixture in advance, and then stirring for 1 hour, wasadded thereto at 0° C., followed by stirring at room temperatureovernight. Furthermore, a mixture of 1-acetylpiperidine-4-carboxylicacid (322 mg), oxalyl chloride (0.168 ml), and DMF in dichloromethane (6ml) which is mixed in advance and was stirred for 1 hour, was addedthereto at 0° C., followed by stirring at room temperature for 3 hours.Furthermore, a mixture of 1-acetylpiperidine-4-carboxylic acid (322 mg),oxalyl chloride (0.168 ml), and DMF in dichloromethane (6 ml) which ismixed in advance and was stirred for 1 hour, was added thereto at 0° C.,followed by stirring at room temperature overnight. CHCl₃ and water wereadded to the reaction mixture, and the insoluble matter was removed byfiltration. The organic layer was washed with water and saturated brine,dried over Na₂SO₄, and then concentrated under reduced pressure. Theobtained residue was mixed with MeOH, and NaHCO₃ was added thereto,followed by stirring at room temperature overnight. The reaction mixturewas concentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (MeOH/CHCl₃) to obtain1-acetyl-N-[5-(2-fluoro-3-formylphenyl)pyrimidin-2-yl]piperidine-4-carboxyamide(363 mg).

Preparation Example 766

tert-Butyl 4-(2-iodoethyl)piperidine-1-carboxylate (6.75 g) was mixedwith dichloromethane (90 ml), and benzyl4-hydroxypiperidine-1-carboxylate (4.0 g), silver trifluoromethanesulfonate (10.3 g), and 2,6-di-tert-butylpyridine (12 ml) was addedthereto, followed by stirring at room temperature overnight. Thereaction mixture was filtered using Celite as a filtration adjuvant, andthe filtrate was concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (hexane/EtOAc)to obtain tert-butyl4-[2-({1-[(benzyloxy)carbonyl]piperidin-4-yl}oxy)ethyl]piperidine-1-carboxylate(3.4 g).

Preparation Example 767

5-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-(piperidin-4-ylmethoxy)pyrimidine(200 mg) was mixed with THF (4 ml), and ethylisocyanate (91 mg) wasadded thereto, followed by stirring at room temperature overnight. A 1MTBAF/THF solution (1 ml) was added to the reaction mixture, followed byfurther stirring at room temperature for 3 hours. Water and EtOAc wereadded to the reaction mixture, and the organic layer was dried overNa₂SO₄ and concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (MeOH/CHCl₃) to obtainN-ethyl-4-[({5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}oxy)methyl]piperidine-1-carboxyamide(159.3 mg).

Preparation Example 772

5-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-(piperazin-1-yl)pyrimidine(500 mg) was mixed with dichloromethane (10 ml), and DIPEA (482 mg) and2-chloroethanesulfonyl chloride (304 mg) were added thereto at 0° C.,followed by stirring at 0° C. for 1.5 hours. CHCl₃ and water were addedto the reaction mixture, and the organic layer was washed with water andsaturated brine, dried over Na₂SO₄, and then concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (EtOAc/hexane) to obtain5-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-2-[4-(vinylsulfonyl)piperazin-1-yl]pyrimidine(360 mg).

Preparation Example 776

1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine(140 mg) was mixed with DCE (4 ml), and ethanesulfonyl chloride (122 mg)and TEA (145 mg) were added thereto, followed by stirring at roomtemperature for 2 hours. CHCl₃ and water were added to the reactionmixture, and the organic layer was dried over Na₂SO₄ and concentratedunder reduced pressure. The obtained residue was mixed with THF (4 ml),and a 1M TBAF/THF solution (0.9 ml) was added thereto, followed bystirring at room temperature for 2 hours. EtOAc and water were added tothe reaction mixture, and the organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (EtOAc/hexane) to obtain{3-[4-(ethylsulfonyl)piperazin-1-yl]-2-fluorophenyl}methanol (123.9 mg).

Preparation Example 791

4-Nitrophenyl4-[({5-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]pyrimidin-2-yl}oxy)methyl]piperidine-1-carboxylate(200 mg) was mixed with NMP (5 ml), and isopropyl amine (0.3 ml) wasadded thereto, followed by stirring at 70° C. for 6 hours. iPrNH₂ (0.3ml) was added to the reaction mixture, followed by stirring at 70° C.overnight. iPrNH₂ (0.4 ml) was added to the reaction mixture, followedby stirring at 70° C. for 3 hours. The reaction mixture was cooled toroom temperature and concentrated under reduced pressure, and then a 1Maqueous NaOH solution and EtOAc were added thereto. The organic layerwas concentrated under reduced pressure. The obtained residue was mixedwith THF (4 ml), and a 1M TBAF/THF solution (0.7 ml) was added thereto,followed by stirring at room temperature for 2 hours. EtOAc and waterwere added to the reaction mixture, and the organic layer was dried overNa₂SO₄ and concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (EtOAc/hexane/MeOH/CHCl₃)to obtain4-[({5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}oxy)methyl]-N-isopropylpiperidine-1-carboxyamide(107.4 mg).

Preparation Example 793

tert-Butyl 3-(pyridin-4-ylmethoxy)azetidine-1-carboxylate (4.8 g) wasmixed with acetic acid (25 ml) and EtOAc (25 ml), and 10%platinum/carbon was added thereto under argon atmosphere, followed bystirring at room temperature overnight under hydrogen atmosphere of 1atm. The reaction mixture was filtered using Celite as a filtrationadjuvant, and the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (CHCl₃/MeOH) toobtain tert-butyl 3-(piperidin-4-ylmethoxy)azetidine-1-carboxylate (4.8g).

Preparation Example 796

Benzyl 3-oxopiperazine-1-carboxylate (400 mg) and3-(bromomethyl)pyridine hydrobromide (647 mg) were mixed with DMF (8ml), and sodium hydride (55% suspended in oil) (194 mg) was addedthereto at 0° C., followed by stirring at room temperature for 3 hours.Water and CHCl₃ were added to the reaction mixture at 0° C., and theorganic layer was washed with water and saturated brine, dried overanhydrous sodium carbonate, and concentrated under reduced pressure. Theobtained residue was purified by basic silica gel column chromatography(EtOAc/hexane) to obtain benzyl3-oxo-4-(pyridin-3-ylmethyl)piperazine-1-carboxylate (345 mg).

Preparation Example 801

2-(2-Fluoro-3-{4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]piperazin-1-yl}benzyl)-1H-isoindole-1,3(2H)-dione(135 mg) was suspended in EtOH (3 ml), and hydrazine hydrate (67 mg) wasadded thereto, followed by stirring at 80° C. overnight. The reactionmixture was concentrated under reduced pressure, and the obtainedresidue was purified by silica gel column chromatography (28% aqueousammonia/MeOH/CHCl₃) to obtain1-(2-fluoro-3-{4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]piperazin-1-yl}phenyl)methanamine(100 mg).

Preparation Example 803

tert-Butyl 3-hydroxyazetidine-1-carboxylate (1.0 g) and6-methylpyridin-3-ol (570 mg) were mixed with THF (10 ml), andtriphenylphosphine (2.3 g) was added thereto. A 1.9 M DIAD/toluenesolution (4.5 ml) was added dropwise thereto, followed by stirring at55° C. overnight. The reaction mixture was concentrated under reducedpressure, and EtOAc and 1M hydrochloric acid were added thereto. Theaqueous layer was adjusted to pH of around 10 by the addition of a 4Maqueous NaOH solution, followed by extraction with CHCl₃. The organiclayer was dried over Na₂SO₄ and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(CHCl₃/MeOH). The purified product thus obtained was mixed with DCE (6ml), and TFA (3 ml) was added thereto, followed by stirring at roomtemperature for 5 hours. The reaction mixture was concentrated underreduced pressure, and then CHCl₃ and a 1 M aqueous NaOH solution wereadded thereto. The organic layer was dried over Na₂SO₄ and thenconcentrated under reduced pressure to obtain5-(azetidin-3-yloxy)-2-methylpyridine (269 mg).

Preparation Example 805

4-Bromo-2,6-dimethylpyridine (2 g) was mixed with THF (30 ml) and cooledto −78° C. under argon atmosphere. A 1.65 M n-butyl lithium/hexanesolution (8.5 ml) was added dropwise thereto, followed by stirring at−78° C. for 10 minutes, and DMF (1.3 ml) was added thereto. The reactionmixture was warmed to 0° C. over 1 hour, followed by stirring at 0° C.for 1 hour. Water and EtOAc were added to the reaction mixture, and theorganic layer was dried over Na₂SO₄, and the reaction mixture wasconcentrated under reduced pressure. The obtained residue was mixed withMeOH (30 ml), and NaBH₄ (610 mg) was added thereto, followed by stirringat room temperature for 1 hour. The reaction mixture was concentratedunder reduced pressure, and CHCl₃ and water were added to the obtainedresidue. The organic layer was dried over Na₂SO₄ and concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (CHCl₃/MeOH) to obtain (2,6-dimethylpyridin-4-yl)methanol(457 mg).

Preparation Example 806

(2,6-Dimethylpyridin-4-yl)methanol (457 mg) was mixed with DCE (8 ml),and thionyl chloride (0.6 ml) and DMF (19 mg) were added thereto,followed by stirring at room temperature for 1 hour. The reactionmixture was concentrated under reduced pressure to obtain4-(chloromethyl)-2,6-dimethylpyridine hydrochloride (567 mg).

Preparation Example 807

1-(2-tert-Butoxypyridin-4-yl)-4-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine(3.14 g) was mixed with CH₂Cl₂ (50 ml), and TFA (5.1 ml) was addedthereto, followed by stirring at room temperature overnight. Thereaction mixture was concentrated under reduced pressure, and theresidue was mixed with MeOH (2 ml). A 8 M NH₃/MeOH solution (10 ml) wasadded thereto at 0° C., followed by stirring at room temperature for 2hours. The solid in the reaction mixture was collected by filtration,washed with MeOH, and dried at 50° C. under reduced pressure to obtain4-{4-[2-fluoro-3-(hydroxymethyl)phenyl]piperazin-1-yl}pyridin-2(1H)-one(1.76 g).

Preparation Example 809

tert-Butyl 4-[1-(diphenylmethyl)azetidin-3-yl]piperidine-1-carboxylate(1.9 g) was mixed with MeOH (50 ml), and 1M hydrochloric acid (5.1 ml)and 20% palladium carbon hydroxide (600 mg) were added thereto, followedby stirring at room temperature for 4 hours under hydrogen atmosphere of3 atm. After returning to normal pressure under argon atmosphere, a 1Maqueous NaOH solution (1 ml) was added thereto. The reaction mixture wasfiltered using Celite as a filtration adjuvant, and the filtrate wasconcentrated under reduced pressure. CHCl₃ and a 1M aqueous NaOHsolution were added to the obtained residue, and the organic layer wasdried over Na₂SO₄ and then concentrated under reduced pressure. Theobtained residue was purified by basic silica gel column chromatography(CHCl₃/MeOH) to obtain tert-butyl4-(azetidin-3-yl)piperidine-1-carboxylate (1.1 g).

Preparation Example 810

tert-Butyl4-{1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine-1-carboxylate(2 g) was mixed with CH₂Cl₂ (20 ml), and TFA (5 ml) was added thereto,followed by stirring at room temperature for 3 hours. The reactionmixture was concentrated under reduced pressure. The obtained residuewas mixed with CH₂Cl₂ (30 ml), and TEA (6 ml) and TBSC1 (2.5 g) wereadded thereto, followed by stirring at 60° C. overnight. Water was addedto the reaction mixture, and the organic layer was dried over Na₂SO₄ andthen concentrated under reduced pressure. The obtained residue was mixedwith MeOH (20 ml), and a 1M aqueous NaOH solution (5 ml), followed bystirring at room temperature for 1 hour. The reaction mixture wasconcentrated under reduced pressure, CHCl₃ and water were added to theobtained residue, and the organic layer was dried over Na₂SO₄ and thenconcentrated under reduced pressure. The obtained residue was purifiedby basic silica gel column chromatography (hexane/EtOAc) to obtain4-{1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine(673 mg).

Preparation Example 821

tert-Butyl 3-{[6-(hydroxymethyl)pyridin-3-yl]oxy}azetidine-1-carboxylate(198 mg) was mixed with THF (3 ml), and sodium hydride (55% suspended inoil) (50 mg) was added thereto at 0° C., followed by stirring at 0° C.for 30 minutes. Methyl iodide (0.4 ml) was added to the reactionmixture, followed by stirring at room temperature for 3 hours. EtOAc andwater were added to the reaction mixture, and the organic layer wasdried over Na₂SO₄, and concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (CHCl₃/MeOH).The purified product thus obtained was mixed with DCE (2.8 ml), and TFA(902 mg) was added thereto, followed by stirring at room temperature for5 hours. CHCl₃ and a 1 M aqueous NaOH solution were added to thereaction mixture, and the organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure. The obtained residue was purifiedby basic silica gel column chromatography (CHCl₃/MeOH) to obtain5-(azetidin-3-yloxy)-2-(methoxymethyl)pyridine.

Preparation Example 830

(3-{3-[(6-tert-Butoxypyridin-3-yl)oxy]azetidin-1-yl}-2-fluorophenyl)methanol(760 mg) was mixed with dichloromethane (5 ml), and TFA (2 ml) was addedthereto, followed by stirring at room temperature for 3 hours. Thereaction mixture was concentrated under reduced pressure, and a 1Maqueous NaOH solution and CHCl₃ were added thereto. The organic layerwas dried over Na₂SO₄ and then concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(CHCl₃/MeOH) to obtain5-({1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)pyridin-2(1H)-one(428 mg).

Preparation Example 834

4-{1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine(120 mg) and triethylamine (145 mg) were mixed with dichloromethane (3ml), and propanoyl chloride (48 mg) was added thereto, followed bystirring at room temperature for 1 hour. A 1M aqueous NaOH solution andCHCl₃ were added to the reaction mixture, and the organic layer wasdried over Na₂SO₄ and concentrated under reduced pressure. The obtainedresidue was mixed with THF (3 ml), and a 1M TBAF/THF (0.5 ml) solutionwas added thereto, followed by stirring at room temperature for 1 hour.A saturated aqueous ammonium chloride solution and EtOAc were added tothe reaction mixture, and the organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (CHCl₃/MeOH) to obtain1-(4-{1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}piperidin-1-yl)propan-1-one(98 mg).

Preparation Example 836

4-{1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine(120 mg) and methoxy acetic acid (47 mg) was mixed with dichloromethane(3 ml), and WSC hydrochloride (100 mg) and HOBt (70 mg) was addedthereto, followed by stirring at room temperature for 3 hours. A 1Maqueous NaOH solution and CHCl₃ were added to the reaction mixture, andthe organic layer was dried over Na₂SO₄ and concentrated under reducedpressure. The obtained residue was mixed with THF (3 ml), and a 1MTBAF/THF solution (0.66 ml) was added thereto, followed by stirring atroom temperature for 1 hour. EtOAc and a saturated aqueous ammoniumchloride solution were added to the reaction mixture, and the organiclayer was dried over Na₂SO₄ and concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(hexane/EtOAc) to obtain1-(4-{1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}piperidin-1-yl)-2-methoxyethanone(106 mg).

Preparation Example 840

4-{4-[2-Fluoro-3-(hydroxymethyl)phenyl]piperazin-1-yl}pyridin-2(1H)-one(300 mg) was suspended in DMF (7.5 ml), and potassium carbonate (273mg), 2-bromoethylmethyl ether (275 mg), and tetrabutylammonium iodide(37 mg) were added thereto, followed by stirring at 60° C. overnight.Water and CHCl₃ were added to the reaction mixture, and the organiclayer was washed with saturated brine and then dried over Na₂SO₄. Thesolvent was evaporated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (MeOH/CHCl₃) to obtain(2-fluoro-3-{4-[2-(2-methoxyethoxy)pyridin-4-yl]piperazin-1-yl}phenyl)methanol(104 mg).

Preparation Example 841

Benzyl 3-hydroxyazetidine-1-carboxylate (2.3 g) and6-tert-butoxypyridin-3-ol (1.5 g) were mixed with THF (25 ml), andtriphenylphosphine (4 g) was added thereto. A 1.9 M DIAD/toluenesolution (8 ml) was added dropwise thereto, followed by stirring at 55°C. overnight. The reaction mixture was concentrated under reducedpressure. The obtained residue was mixed with ethanol (25 ml), and 10%palladium carbon (800 mg) were added thereto, followed by stirring atroom temperature for 5 hours under hydrogen atmosphere. The reactionmixture was filtered using Celite as a filtration adjuvant, and thefiltrate was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (CHCl₃/MeOH) to obtain5-(azetidin-3-yloxy)-2-tert-butoxypyridine (595 mg).

Preparation Example 842

5-({1-[2-Fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)pyridin-2(1H)-one(160 mg) was mixed with DMF (3 ml), and methyl iodide (114 mg) andpotassium carbonate (200 mg) were added thereto, followed by stirring at60° C. for 2 hours. The reaction mixture was concentrated under reducedpressure, and to the residue were added CHCl₃ and water. The organiclayer was dried over Na₂SO₄ and then concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (CHCl₃/MeOH) to obtain5-({1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)-1-methylpyridin-2(1H)-one(106 mg).

Preparation Example 845

4-({1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}oxy)piperidine(250 mg) and dioxane (7 ml) were mixed, and methyl5-bromopyridine-2-carboxylate (170 mg), palladium acetate (II)(15 mg),dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (60 mg), andtripotassium phosphate (400 mg) were added thereto, followed by stirring100° C. for 48 hours. The reaction mixture was cooled to roomtemperature, and filtered by the addition of CHCl₃ and Celite, and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/EtOAc). Thepurified product thus obtained was mixed with THF (5 ml), and a 1.0MTBAF/THF solution (0.63 ml) was added thereto, followed by stirring atroom temperature for 1 hour. A saturated aqueous ammonium chloridesolution and CHCl₃ were added to the reaction mixture, and the organiclayer was dried over Na₂SO₄ and then concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (CHCl₃/MeOH) to obtain methyl5-[4-({1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)piperidin-1-yl]pyridine-2-carboxylate (92 mg).

Preparation Example 847

tert-Butyl4-{1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine-1-carboxylate(2.9 g) and dichloromethane (29 ml) were mixed, and TFA (7.3 ml) wasadded thereto, followed by stirring at room temperature for 3 hours. Thereaction mixture was concentrated under reduced pressure, and CHCl₃ anda saturated aqueous sodium hydrogen carbonate solution were addedthereto. The aqueous layer was concentrated under reduced pressure, andCHCl₃ was added to the residue, followed by stirring and filtrating. Thefiltrate was dried over Na₂SO₄ and then concentrated under reducedpressure. The obtained residue was purified by basic silica gel columnchromatography (CHCl₃/MeOH) to obtain{2-fluoro-3-[3-(piperidin-4-yl)azetidin-1-yl]phenyl}methanol (1.25 g).

Preparation Example 853

5-{4-[2-Fluoro-3-(hydroxymethyl)phenyl]piperazin-1-yl}pyridin-2(1H)-one(352 mg) and DMF (10 ml) were mixed, and potassium carbonate (240 mg)and methyl iodide (200 mg) were added thereto, followed by stirring at60° C. overnight. Methyl iodide (49 mg) and potassium carbonate (48.1mg) were added thereto, followed by stirring at 60° C. for 4 hours. Thereaction mixture was cooled to room temperature, and water and CHCl₃were added thereto at 0° C. The organic layer was washed with water andsaturated brine, and then dried over Na₂SO₄, and the solvent wasevaporated under reduced pressure. The obtained residue was purified bysilica gel column chromatography (CHCl₃/MeOH) to obtain5-{4-[2-fluoro-3-(hydroxymethyl)phenyl]piperazin-1-yl}-1-methylpyridin-2(1H)-one(256 mg).

Preparation Example 855

6-Iodoimidazo[1,2-a]pyridine (400 mg), tert-butyl3-hydroxyazetidine-1-carboxylate (500 mg), and toluene (2 ml) weremixed, and copper iodide (I) (40 mg), 1,10-phenanthroline (60 mg), andcesium carbonate (1 g) were added thereto, followed by stirring at 100°C. overnight. CHCl₃ and water were added to the reaction mixture, andthe organic layer was dried over Na₂SO₄ and then concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (CHCl₃/MeOH). The purified product thus obtained wasmixed with dichloromethane (5 ml), and TFA (1.5 ml) was added thereto,followed by stirring at room temperature for 3 hours. The reactionmixture was concentrated under reduced pressure, and the residue waspurified by basic silica gel column chromatography (CHCl₃/MeOH) toobtain 6-(azetidin-3-yloxy)imidazo[1,2-a]pyridine (189 mg).

Preparation Example 857

tert-Butyl 3-oxoazetidine-1-carboxylate (1 g) and THF (20 ml), which hadbeen cooled to 0° C., were mixed, and a 1.12M methylmagnesiumbromide/THF solution (10 ml) was added thereto, followed by stirring atthe same temperature for 1 hour. Water and EtOAc were added to thereaction mixture, the organic layer was dried over Na₂SO₄, and thesolvent was concentrated under reduced pressure. The obtained residuewas purified by silica gel column chromatography (hexane/EtOAc) toobtain tert-butyl 3-hydroxy-3-methylazetidine-1-carboxylate (1.0 g).

Preparation Example 859

5-(Chloromethyl)-2-methylpyridine hydrochloride (1.13 g) and DMF (9 ml)were mixed, and triphenylphosphine (1.67 g) and sodium iodide (5 mg)were added thereto, followed by stirring at 90° C. for 6 hours. Thereaction mixture was cooled to room temperature, and the precipitatedsolid was collected by filtration and washed with toluene to obtain[(6-methylpyridin-3-yl)methyl](triphenyl)phosphonium chloridehydrochloride (2.18 g).

Preparation Example 860

Under argon atmosphere, (2-bromopyridin-4-yl)methanol (2.53 g),cyclopropylboronic acid (3.6 g), tripotassium phosphate (10 g),tricyclohexylphosphine (750 mg), toluene (60 ml), and water (3 ml) weremixed, and palladium acetate (II) (300 mg) were added thereto, followedby stirring at 100° C. for 5 hours. Cyclopropylboronic acid (1.8 g) wasadded thereto, followed by stirring at 100° C. for 2 hours. The reactionmixture was concentrated under reduced pressure, and CHCl₃ and waterwere added thereto. The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (hexane/EtOAc) to obtain(2-cyclopropylpyridin-4-yl)methanol (602 mg).

Preparation Example 893

Under argon atmosphere,[(3-bromo-2-fluorobenzyl)oxy](tert-butyl)dimethylsilane (5.5 g),3-[(benzyloxy)methyl]azetidine (2.5 g), and toluene (50 ml) were mixed,and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one palladium (3:2) (900 mg),BINAP (1.8 g), and sodium tert-butoxide (2.5 g) were added thereto,followed by stirring at 90° C. for 3 hours. The reaction mixture wascooled to room temperature, and EtOAc were added thereto, followed byfiltering using Celite as a filtration adjuvant. The filtrate wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography (hexane/EtOAc). The purified productthus obtained was mixed with EtOH (40 ml), and 10% palladium carbon (1g) was added thereto, followed by stirring at room temperature overnightunder hydrogen atmosphere of 1 atm and filtering using Celite as afiltration adjuvant. The filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(CHCl₃/MeOH) to obtain{1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}methanol(885 mg).

Preparation Example 894

Under argon atmosphere,4-({1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}oxy)piperidine(500 mg), 5-bromo-2-tert-butoxypyridine (500 mg), and toluene (10 ml)were mixed, and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one palladium (3:2)(80 mg), BINAP (160 mg), sodium tert-butoxide (200 mg) were addedthereto, followed by stirring at 90° C. for 3 hours.

The reaction mixture was cooled to room temperature, and EtOAc was addedthereto, followed by filtering using Celite as a filtration adjuvant.The filtrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (hexane/EtOAc). Thepurified product thus obtained was mixed with dichloromethane (5 ml),and TFA (2 ml) was added thereto, followed by stirring at roomtemperature overnight. The reaction mixture was concentrated underreduced pressure, and to the residue were added MeOH (3 ml) and a 1Maqueous NaOH solution (2.5 ml), followed by stirring at room temperaturefor 1 hour. 1M hydrochloric acid (2.5 ml) was added thereto, and thereaction mixture was concentrated under reduced pressure. To the residuewere added CHCl₃ and water, and the organic layer was dried over Na₂SO₄and concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (CHCl₃/MeOH) to obtain5-[4-({1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)piperidin-1-yl]pyridin-2(1H)-one(306 mg).

Preparation Example 922

tert-Butyl 3-{[6-(hydroxymethyl)pyridin-3-yl]oxy}azetidine-1-carboxylate(242 mg) and THF (3 ml) were mixed, and triethylamine (182 mg) andmethanesulfonyl chloride (147 mg) were added thereto, followed bystirring at room temperature for 1 hour. In another flask, THF (3 ml)and EtOH (237 mg) were mixed, and NaH was added thereto, followed bystirring at room temperature for 10 minutes. The reaction mixtureprepared immediately before was added thereto, followed by stirring atroom temperature for 1 hour. Water and EtOAc were added to the reactionmixture, and the organic layer was concentrated under reduced pressure.DCE (4 ml) and TFA (1 ml) were added to the obtained residue, followedby stirring at room temperature for 5 hours, and then concentratingunder reduced pressure. CHCl₃ and a 1M aqueous NaOH solution were addedto the residue, and the organic layer was dried over Na₂SO₄ and thenconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (CHCl₃/MeOH) to obtain5-(azetidin-3-yloxy)-2-(ethoxymethyl)pyridine (131 mg).

Preparation Example 926

{1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}methylmethanesulfonate(150 mg), 6-methylpyridin-3-ol (70 mg), and DMF (2 ml) were mixed, andpotassium carbonate (120 mg) were added thereto, followed by stirring at80° C. for 6 hours. The reaction mixture was concentrated under reducedpressure, and CHCl₃ and a saturated aqueous sodium hydrogen carbonatesolution were then added thereto. The organic layer was dried overNa₂SO₄ and concentrated under reduced pressure. THF (2 ml) and a 1MTBAF/THF solution (0.6 ml) were added to the obtained residue, followedby stirring at room temperature for 1 hour. CHCl₃ and a saturatedaqueous ammonium chloride solution were added to the reaction mixture,and the organic layer was dried over Na₂SO₄ and then concentrated underreduced pressure. The obtained residue was purified by silica gel columnchromatography (hexane/EtOAc) to obtain[2-fluoro-3-(3-{[(6-methylpyridin-3-yl)oxy]methyl}azetidin-1-yl)phenyl]methanol(74 mg).

Preparation Example 938

TFA (0.5 ml) was added to a mixture of[3-(3-{[(6-tert-butoxypyridin-3-yl)oxy]methyl}azetidin-1-yl)-2-fluorophenyl]methanol(146 mg) and dichloromethane (1 ml), followed by stirring at roomtemperature for 3 hours. The reaction mixture was concentrated underreduced pressure and the residue was purified by basic silica gel columnchromatography (CHCl₃/methanol). The purified product thus obtained wasmixed with DMF (2 ml), and potassium carbonate (100 mg) and methyliodide (68 mg) was added thereto, followed by stirring at roomtemperature for 5 hours. The reaction mixture was concentrated underreduced pressure, and CHCl₃ and water were added to the residue. Theorganic layer was dried over Na₂SO₄ and then concentrated under reducedpressure. The obtained residue was purified by silica gel columnchromatography (CHCl₃/methanol) to obtain5-({1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}methoxy)-1-methylpyridin-2(1H)-one(82 mg).

The compounds of Preparation Examples shown in the tables below wereprepared using the respective corresponding starting materials in thesame manner as the methods of Preparation Examples above. Thestructures, the preparation methods, and the physicochemical data forthe compounds of Preparation Examples are shown in the tables below.

TABLE 3 Rf Syn Structure 1 R12

2 R12

3 R12

4 R12

5 R12

6 R12

7 R12

8 R12

9 R12

10 R12

11 R12

12 R12

13 R12

14 R12

TABLE 4 Rf Syn Structure 15 R12

16 R12

17 R12

18 R12

19 R12

20 R12

21 R12

22 R12

23 R12

24 R12

25 R12

26 R12

27 R12

28 R12

TABLE 5 Rf Syn Structure 29 R12

30 R12

31 R12

32 R32

33 R33

34 R33

35 R33

36 R33

37 R33

38 R38

39 R39

40 R41

41 R41

42 R42

43 R42

44 R44

TABLE 6 Rf Syn Structure 45 R45

46 R45

47 R45

48 R48

49 R50

50 R50

51 R50

52 R50

53 R54

54 R54

55 R54

56 R54

57 R57

58 R58

59 R58

60 R60

61 R60

62 R62

TABLE 7 Rf Syn Structure 63 R63

64 R63

65 R63

66 R63

67 R67

68 R67

69 R69

70 R70

71 R81

72 R81

73 R81

74 R81

75 R81

76 R81

77 R81

78 R81

TABLE 8 Rf Syn Structure 79 R81

80 R81

81 R81

82 R81

83 R81

84 R135

85 R135

86 R135

87 R135

88 R135

89 R135

90 R135

91 R135

92 R135

TABLE 9 Rf Syn Structure 93 R135

94 R135

95 R135

96 R135

97 R135

98 R135

99 R135

100 R135

101 R135

102 R135

103 R135

104 R135

105 R135

106 R135

107 R135

108 R135

TABLE 10 Rf Syn Structure 109 R135

110 R135

111 R135

112 R135

113 R135

114 R135

115 R135

116 R135

117 R135

118 R135

119 R135

120 R135

121 R135

122 R135

TABLE 11 Rf Syn Structure 123 R135

124 R135

125 R135

126 R135

127 R135

128 R135

129 R135

130 R135

131 R135

132 R135

133 R135

134 R135

135 R135

136 R135 137 R135

138 R135

TABLE 12 Rf Syn Structure 139 R135

140 R135

141 R135

142 R135

143 R135

144 R135

145 R135

146 R135

147 R135

148 R135

149 R135

150 R135

151 R135

152 R135

TABLE 13 Rf Syn Structure 153 R135

154 R135

155 R135

156 R135

157 R135

158 R159

159 R159

160 R159

161 R162

162 R162

163 R163

164 R174

165 R174

166 R174

TABLE 14 Rf Syn Structure 167 R174

168 R174

169 R174

170 R174

171 R174

172 R174

173 R174

174 R174

175 R174

176 R177

177 R177

178 R177

179 R177

180 R177

181 R177

182 R182

TABLE 15 Rf Syn Structure 183 R228

184 R228

185 R228

186 R228

187 R228

188 R228

189 R228

190 R228

191 R228

192 R228

193 R228

194 R228

195 R228

196 R228

197 R228

198 R228

TABLE 16 Rf Syn Structure 199 R228

200 R228

201 R228

202 R228

203 R228

204 R228

205 R228

206 R228

207 R228

208 R228

209 R228

210 R228

211 R228

212 R228

213 R228

214 R228

215 R228

216 R228

TABLE 17 Rf Syn Structure 217 R228

218 R228

219 R228

220 R228

221 R228

222 R228

223 R228

224 R228

225 R228

226 R228

227 R228

228 R228

229 R228

230 R228

231 R228

232 R228

233 R228

234 R228

TABLE 18 Rf Syn Structure 235 R228

236 R228

237 R228

238 R228

239 R228

240 R228

241 R228

242 R228

243 R228

244 R228

245 R228

246 R228

247 R228

248 R228

249 R228

250 R228

TABLE 19 Rf Syn Structure 251 R228

252 R228

253 R228

254 R228

255 R228

256 R228

257 R228

258 R228

259 R228

260 R228

261 R228

262 R228

263 R228

264 R228

265 R228

266 R228

TABLE 20 Rf Syn Structure 267 R228

268 R228

269 R228

270 R228

271 R228

272 R228

273 R228

274 R228

275 R228

276 R228

277 R228

278 R228

279 R228

280 R228

281 R228

282 R228

283 R228

284 R285

TABLE 21 Rf Syn Structure 285 R285

286 R285

287 R285

288 R285

289 R285

290 R290

291 R290

292 R285

293 R294

294 R294

295 R294

296 R297

297 R297

298 R297

299 R297

300 R297

TABLE 22 Rf Syn Structure 301 R301

302 R302

303 R304

304 R304

305 R305

306 R306

307 R307

308 R309

309 R309

310 R336

311 R336

312 R326

313 R336

314 R336

315 R336

316 R336

TABLE 23 Rf Syn Structure 317 R336

318 R336

319 R336

320 R336

321 R336

322 R336

323 R336

324 R336

325 R336

326 R336

327 R336

328 R336

329 R336

330 R336

331 R336

332 R336

TABLE 24 Rf Syn Structure 333 R336

334 R336

335 R336

336 R336

337 R336

338 R336

339 R336

340 R336

341 R341

342 R343

343 R343

344 R343

345 R343

346 R343

TABLE 25 Rf Syn Structure 347 R347

348 R347

349 R347

350 R347

351 R347

352 R376

353 R376

354 R376

355 R376

356 R376

357 R376

358 R376

359 R376

360 R376

TABLE 26 Rf Syn Structure 361 R376

362 R159

363 R376

364 R376

365 R376

366 R376

367 R376

368 R376

369 R376

370 R376

371 R376

372 R376

373 R376

374 R376

TABLE 27 Rf Syn Structure 375 R376

376 R376

377 R376

378 R376

379 R376

380 R376

381 R376

382 R376

383 R376

384 R376

385 R376

386 R376

387 R376

388 R376

TABLE 28 Rf Syn Structure 389 R376

390 R376

391 R376

392 R376

393 R376

394 R376

395 R376

396 R376

397 R376

398 R376

399 R376

400 R376

401 R376

402 R376

TABLE 29 Rf Syn Structure 403 R376

404 R376

405 R376

406 R376

407 R376

408 R376

409 R376

410 R376

411 R376

412 R376

413 R376

414 R376

415 R376

416 R376

TABLE 30 Rf Syn Structure 417 R376

418 R376

419 R376

420 R376

421 R376

422 R376

423 R376

424 R376

425 R376

426 R376

427 R376

428 R376

429 R376

430 R376

TABLE 31 Rf Syn Structure 431 R376

432 R376

433 R376

434 R376

435 R376

436 R376

437 R376

438 R376

439 R376

440 R376

441 R376

442 R376

443 R376

444 R376

TABLE 32 Rf Syn Structure 445 R376

446 R376

447 R376

448 R376

449 R376

450 R376

451 R376

452 R376

453 R376

454 R376

455 R376

456 R376

457 R376

458 R478

TABLE 33 Rf Syn Structure 459 R478

460 R478

461 R478

462 R478

463 R478

464 R478

465 R478

466 R478

467 R478

468 R478

469 R478

470 R478

471 R478

472 R478

473 R478

474 R478

475 R478

476 R478

TABLE 34 Rf Syn Structure 477 R478

478 R478

479 R478

480 R478

481 R478

482 R478

483 R478

484 R478

485 R478

486 R478

487 R478

488 R478

489 R478

490 R478

TABLE 35 Rf Syn Structure 491 R478

492 R478

493 R478

494 R478

495 R478

496 R478

497 R478

498 R478

499 R478

500 R478

501 R478

502 R478

503 R478

504 R478

TABLE 36 Rf Syn Structure 505 R478

506 R478

507 R508

508 R508

509 R508

510 R508

511 R514

512 R514

513 R514

514 R514

515 R516

516 R516

517 R516

518 R518

519 R518

520 R518

TABLE 37 Rf Syn Structure 521 R518

522 R518

523 R518

524 R518

525 R518

526 R518

527 R518

528 R518

529 R548

530 R548

531 R548

532 R548

533 R548

534 R548

535 R548

536 R548

TABLE 38 Rf Syn Structure 537 R548

538 R548

539 R548

540 R548

541 R548

542 R548

543 R548

544 R548

545 R548

546 R548

547 R548

548 R548

549 R548

550 R548

551 R548

552 R548

553 R548

554 R548

TABLE 39 Rf Syn Structure 555 R548

556 R548

557 R548

558 R548

559 R548

560 R548

561 R563

562 R563

563 R563

564 R564

565 R177

566 R568

567 R568

568 R568

569 R568

570 R568

TABLE 40 Rf Syn Structure 571 R568

572 R572

573 R573

574 R574

575 R574

576 R574

577 R581

578 R581

579 R581

580 R581

581 R581

582 R582

583 R582

584 R584

585 R584

586 R584

TABLE 41 Rf Syn Structure 587 R584

588 R584

589 R589

590 R589

591 R589

592 R592

593 R593

594 R594

595 R596

596 R596

597 R603

598 R603

599 R603

600 R603

601 R603

602 R603

603 R603

604 R603

TABLE 42 Rf Syn Structure 605 R603

606 R603

607 R603

608 R603

609 R603

610 R603

611 R603

612 R603

613 R613

614 R614

615 R617

616 R617

617 R617

618 R617

TABLE 43 Rf Syn Structure 619 R617

620 R617

621 R306

622 R306

623 R306

624 R306

625 R306

626 R306

627 R306

628 R306

629 R306

630 R631

631 R631

632 R631

633 R631

634 R638

TABLE 44 Rf Syn Structure 635 R638

636 R638

637 R638

638 R638

639 R638

640 R638

641 R638

642 R638

643 R638

644 R638

645 R638

646 R638

647 R638

648 R638

649 R651

650 R651

651 R651

652 R651

TABLE 45 Rf Syn Structure 653 R653

654 R651

655 R651

656 R651

657 R651

658 R651

659 R651

660 R651

661 R651

662 R653

663 R663

664 R663

665 R663

666 R663

669 R671

670 R671

TABLE 46 Rf Syn Structure 671 R671

672 R671

673 R674

674 R674

675 R674

676 R674

677 R677

678 R677

679 R680

680 R680

681 R680

682 R680

683 R680

684 R680

685 R686

686 R686

TABLE 47 Rf Syn Structure 687 R686

688 R686

689 R686

690 R686

691 R686

692 R686

693 R686

694 R686

695 R686

696 R686

697 R686

698 R686

699 R686

700 R686

701 R686

702 R686

TABLE 48 Rf Syn Structure 703 R686

704 R686

705 R686

706 R686

707 R707

708 R707

709 R709

710 R712

711 R712

712 R712

713 R686

714 R686

715 R686

716 R686

717 R686

718 R686

TABLE 49 Rf Syn Structure 719 R686

720 R686

721 R686

722 R686

723 R686

724 R686

725 R686

726 R343

727 R343

728 R343

729 R343

730 R343

731 R343

732 R343

733 R343

734 R343

TABLE 50 Rf Syn Structure 735 R343

736 R343

737 R343

738 R343

739 R343

740 R343

741 R343

742 R343

743 R343

744 R343

745 R343

746 R343

747 R343

748 R343

749 R749

750 R752

TABLE 51 Rf Syn Structure 751 R752

752 R752

753 R754

754 R754

755 R754

756 R754

757 R754

758 R758

759 R758

760 R760

761 R761

762 R766

763 R766

764 R766

765 R766

766 R766

TABLE 52 Rf Syn Structure 767 R767

768 R767

769 R341

770 R341

771 R341

772 R772

773 R776

774 R776

775 R776

776 R776

777 R776

778 R776

779 R776

780 R776

781 R776

782 R776

TABLE 53 Rf Syn Structure 783 R776

784 R776

785 R776

786 R776

787 R776

788 R776

789 R776

790 R776

791 R791

792 R791

793 R793

794 R793

795 R796

796 R796

797 R801

798 R801

TABLE 54 Rf Syn Structure 799 R801

800 R801

801 R801

802 R343

803 R803

804 R803

805 R805

806 R806

807 R807

808 R809

809 R809

810 R810

811 R228

812 R228

TABLE 55 Rf Syn Structure 813 R228

814 R228

815 R228

816 R228

817 R285

818 R285

819 R285

820 R285

821 R821

822 R821

823 R309

824 R347

825 R347

826 R376

827 R376

828 R376

TABLE 56 Rf Syn Structure 829 R376

830 R830

831 R663

832 R677

833 R686

834 R834

835 R834

836 R836

837 R836

838 R776

839 R285

840 R840

841 R841

842 R842

TABLE 57 Rf Data 1 ESI+: 500 2 ESI+: 288 3 ESI+: 288 4 ESI+: 320 5 ESI+:288 6 ESI+: 288 7 ESI+: 218 8 ESI+: 356 9 ESI+: 275 10 ESI+: 289 11ESI+: 272 12 ESI+: 270 13 ESI+: 277 14 ESI+: 340 15 ESI+: 385 16 ESI+:371 17 ESI+: 369 18 ESI+: 461 19 ESI+: 538, 540 20 ESI+: 334 21 ESI+:221 22 ESI+: 286 23 ESI+: 237 24 ESI+: 286 25 ESI+: 286 26 APCI/ESI+:290 27 APCI/ESI+: 306 28 APCI/ESI+: 347 29 APCI/ESI+: 347 30 APCI/ESI+:287 31 APCI/ESI+: 287 32 ESI+: 308 33 EI: 234

TABLE 58 Rf Data 34 EI: 248 35 EI: 248 36 EI: 252 37 EI: 268 38APCI/ESI+: 182 39 EI: 166 40 ESI+: 501 41 ESI+: 444 42 APCI/ESI+: 282 43APCI/ESI+: 296 44 ESI+: 399 45 ESI+: 285 46 ESI+: 299 47 ESI+: 418 48ESI+: 429 49 ESI+: 285 50 ESI+: 200 51 ESI+: 257 52 ESI+: 271 53 ESI+:369 [M]+ 54 ESI+: 284 [M]+ 55 ESI+: 341 [M]+ 56 ESI+: 355 [M]+ 57 ESI+:211 58 ESI+: 251 59 ESI+: 265 60 ESI+: 303 61 ESI+: 303 62 ESI+: 164 63ESI+: 193 64 ESI+: 207 65 ESI+: 165 66 ESI+: 179

TABLE 59 Rf Data 67 ESI+: 460 68 ESI+: 502 69 ESI+: 399 70 ESI+: 364 71ESI+: 290 72 ESI+: 290 73 ESI+: 290 74 ESI+: 290 75 ESI+: 308 76 ESI+:304 77 ESI+: 320 78 ESI+: 333 79 ESI+: 373 80 ESI+: 239 81 ESI+: 288 82APCI/ESI+: 289 83 APCI/ESI+: 289 84 ESI+: 332.15 85 ESI+: 333.09 86ESI+: 341 87 ESI+: 345 88 ESI+: 380 89 ESI+: 334 90 ESI+: 372 91 ESI+:356 92 ESI+: 443 93 APCI/ESI+: 481, 483 94 APCI/ESI+: 288, 290 95APCI/ESI+: 264, 266 96 ESI+: 370 97 ESI+: 532 98 ESI+: 532 99 ESI+: 271

TABLE 60 Rf Data 100 ESI+: 374 101 ESI+: 389 102 ESI+: 317 103 ESI+: 318104 ESI+: 317 105 ESI+: 334 106 ESI+: 443 107 ESI+: 360 108 ESI+: 376109 ESI+: 402 110 ESI+: 375 111 ESI+: 318 112 ESI+: 186 113 ESI+: 166114 ESI+: 360 115 ESI+: 332 116 ESI+: 224 117 ESI+: 460 118 ESI+: 292119 ESI+: 319 120 ESI+: 331 121 ESI+: 331 122 ESI+: 327 123 ESI+: 399124 ESI+: 355 125 ESI+: 441 126 ESI+: 404 127 ESI+: 447 128 ESI+: 454129 ESI+: 399 130 ESI+: 373 131 ESI+: 300 132 ESI+: 274

TABLE 61 Rf Data 133 ESI+: 256 134 ESI+: 274 135 ESI+: 300 136 ESI+: 314137 ESI+: 328 138 ESI+: 348 139 ESI+: 292 140 ESI+: 292 141 ESI+: 274142 APCI/ESI+: 248 143 APCI/ESI+: 318 144 APCI/ESI+: 288 145 ESI+: 306146 APCI/ESI+: 373 147 APCI/ESI+: 306 148 APCI/ESI+: 304 149 APCI/ESI+:336 150 ESI+: 372 151 ESI+: 386 152 ESI+: 290 153 APCI/ESI+: 304 154APCI/ESI+: 390 155 APCI/ESI+: 465 156 APCI/ESI+: 408 157 APCI/ESI+: 278158 ESI+: 388 159 ESI+: 415 160 ESI+: 376 161 ESI+: 277 162 EI: 194 163ESI+: 249 164 ESI+: 341 165 ESI+: 472

TABLE 62 Rf Data 166 ESI+: 594 167 ESI+: 524 168 ESI+: 425 169 ESI+: 495170 ESI+: 245 171 ESI+: 259 172 ESI+: 378 173 ESI+: 417 174 ESI+: 277175 ESI+: 271 176 ESI+: 187 177 ESI+: 332 178 ESI+: 304 179 ESI+: 210180 APCI/ESI+: 254 181 APCI/ESI+: 268 182 EI: 306 183 APCI/ESI+: 488 184APCI/ESI+: 516 185 APCI/ESI+: 488 186 APCI/ESI+: 516 187 APCI/ESI+: 487188 APCI/ESI+: 532 189 APCI/ESI+: 487 190 APCI/ESI+: 488 191 APCI/ESI+:407 192 ESI+: 487 193 APCI/ESI+: 508 194 ESI+: 470 195 APCI/ESI+: 433196 APCI/ESI+: 459 197 APCI/ESI+: 503 198 APCI/ESI+: 326

TABLE 63 Rf Data 199 APCI/ESI+: 479 200 APCI/ESI+: 493 201 APCI/ESI+:479 202 APCI/ESI+: 493 203 APCI/ESI+: 555 204 APCI/ESI+: 555 205APCI/ESI+: 326 206 APCI/ESI+: 370 207 APCI/ESI+: 381 208 APCI/ESI+: 584209 APCI/ESI+: 558 210 ESI+: 502 211 ESI+: 319 212 ESI+: 473 213 ESI+:457 214 ESI+: 355 215 ESI+: 487 216 ESI+: 473 217 ESI+: 437 218 ESI+:493 219 ESI+: 487 220 ESI+: 473 221 ESI+: 473 222 ESI+: 411 223 ESI+:423 224 ESI+: 437 225 ESI+: 402 226 ESI+: 402 227 ESI+: 556 228 ESI+:416 229 ESI+: 430 230 ESI+: 416 231 ESI+: 416

TABLE 64 Rf Data 232 ESI+: 403 233 ESI+: 416 234 ESI+: 416 235 ESI+: 416236 ESI+: 416 237 ESI+: 416 238 ESI+: 408 239 ESI+: 416 240 ESI+: 417241 ESI+: 430 242 ESI+: 427 243 ESI+: 413 244 ESI+: 397 245 ESI+: 389246 ESI+: 390 247 ESI+: 350 248 ESI+: 470 249 ESI+: 398 250 ESI+: 384251 ESI+: 384 252 ESI+: 488 253 ESI+: 402 254 ESI+: 401 255 ESI+: 431256 ESI+: 445 257 ESI+: 459 258 ESI+: 401 259 ESI+: 478 260 APCI/ESI+:487 261 APCI/ESI+: 487 262 APCI/ESI+: 487 263 APCI/ESI+: 487 264APCI/ESI+: 503

TABLE 65 Rf Data 265 ESI+: 503 266 APCI/ESI+: 503 267 APCI/ESI+: 409 268APCI/ESI+: 473 269 APCI/ESI+: 502 270 APCI/ESI+: 502 271 APCI/ESI+: 541272 ESI+: 585 273 ESI+: 535 274 ESI+: 537 275 ESI+: 571 276 ESI+: 438277 ESI+: 523 278 ESI+: 438 279 ESI+: 543 280 ESI+: 529 281 ESI+: 543282 ESI+: 557 283 ESI+: 402 284 APCI/ESI+: 240 285 ESI+: 275 286 ESI+:317 287 ESI+: 331 288 ESI+: 289 289 ESI+: 303 290 ESI+: 250 291 ESI+:250 292 ESI+: 298 293 ESI+: 277 294 ESI+: 270 295 ESI+: 269 296APCI/ESI+: 480, 482 297 EI: 300, 302

TABLE 66 Rf Data 298 ESI+: 319 321 299 ESI+: 257 300 APCI/ESI+: 353 301ESI+: 416 302 ESI+: 286 303 ESI+: 417 304 ESI+: 403 305 APCI/ESI+: 320306 ESI+: 200 307 APCI/ESI+: 174 308 EI: 215 309 EI: 182 310 ESI+: 358311 ESI+: 346 312 ESI+: 343 313 APCI/ESI+: 361 314 APCI/ESI+: 347 315APCI/ESI+: 347 316 ESI+: 375 317 318 ESI+: 493 319 ESI+: 401 320 ESI+:401 321 ESI+: 373 322 ESI+: 516 323 ESI+: 403 324 ESI+: 516 325 ESI+:389 326 ESI+: 342 327 ESI+: 368 328 ESI+: 425 329 ESI+: 439 330 ESI+:451

TABLE 67 Rf Data 331 ESI+: 465 332 ESI+: 451 333 APCI/ESI+: 312 334ESI+: 398 335 ESI+: 398 336 APCI/ESI+: 323 337 APCI/ESI+: 321 338APCI/ESI+: 405 339 APCI/ESI+: 337 340 APCI/ESI+: 335 341 ESI+: 363 342APCI/ESI+: 409 343 APCI/ESI+: 414 344 APCI/ESI+: 398 345 APCI/ESI+: 405346 ESI+: 393 347 FAB+: 286, 288 348 ESI+: 312, 314 349 ESI+: 345 350ESI+: 215 351 FAB+: 266 352 APCI/ESI+: 374 353 APCI/ESI+: 402 354APCI/ESI+: 374 355 APCI/ESI+: 402 356 APCI/ESI+: 373 357 APCI/ESI+: 418358 APCI/ESI+: 374 359 APCI/ESI+: 373 360 ESI+: 358 361 ESI+: 402 362APCI/ESI+: 376 363 APCI/ESI+: 376

TABLE 68 Rf Data 364 APCI/ESI+: 373 365 APCI/ESI+: 394 366 APCI/ESI+:356 367 APCI/ESI+: 319 368 APCI/ESI+: 212 369 APCI/ESI+: 389 370APCI/ESI+: 365 371 APCI/ESI+: 379 372 APCI/ESI+: 365 373 APCI/ESI+: 379374 APCI/ESI+: 441 375 APCI/ESI+: 441 376 APCI/ESI+: 212 377 APCI/ESI+:256 378 APCI/ESI+: 267 379 APCI/ESI+: 444 380 APCI/ESI+: 470 381 ESI+:388 382 ESI+: 407 383 ESI+: 374 384 ESI+: 379 385 ESI+: 374 386 ESI+:338 387 ESI+: 338 388 ESI+: 402 389 ESI+: 402 390 ESI+: 411 391 ESI+:343 392 ESI+: 311 393 ESI+: 325 394 ESI+: 337 395 ESI+: 337 396 ESI+:351

TABLE 69 Rf Data 397 ESI+: 346 398 ESI+: 346 399 ESI+: 325 400 ESI+: 351401 ESI+: 376 402 ESI+: 337 403 ESI+: 311 404 ESI+: 337 405 ESI+: 297406 ESI+: 388 407 ESI+: 296 408 ESI+: 323 409 ESI+: 343 410 ESI+: 309411 ESI+: 323 412 ESI+: 288 413 ESI+: 288 414 ESI+: 302 415 ESI+: 316416 ESI+: 302 417 ESI+: 442 418 ESI+: 350 419 ESI+: 302 420 ESI+: 289421 ESI+: 302 422 ESI+: 302 423 ESI+: 302 424 ESI+: 302 425 ESI+: 294426 ESI+: 302 427 ESI+: 345 428 ESI+: 302 429 ESI+: 289

TABLE 70 Rf Data 430 ESI+: 346 431 ESI+: 346 432 ESI+: 303 433 ESI+: 316434 ESI+: 313 435 ESI+: 315 436 ESI+: 285 437 ESI+: 299 438 ESI+: 287439 ESI+: 301 440 ESI+: 303 441 ESI+: 289 442 ESI+: 388 443 ESI+: 356444 ESI+: 284 445 EI: 150 446 APCI/ESI+: 373 447 APCI/ESI+: 373 448APCI/ESI+: 373 449 APCI/ESI+: 373 450 APCI/ESI+: 389 451 APCI/ESI+: 389452 APCI/ESI+: 389 453 APCI/ESI+: 295 454 APCI/ESI+: 388 455 APCI/ESI+:388 456 ESI+: 324 457 ESI+: 324 458 ESI+: 242 459 ESI+: 341 460 ESI+:132 461 ESI+: 276 462 ESI+: 494

TABLE 71 Rf Data 463 ESI+: 424 464 ESI+: 432 465 ESI+: 432 466 ESI+: 235467 ESI+: 256 468 ESI+: 219 469 ESI+: 249 470 ESI+: 223 471 ESI+: 249472 ESI+: 279 473 ESI+: 185 474 ESI+: 199 475 ESI+: 318 476 ESI+: 189477 ESI+: 175 478 ESI+: 250 479 ESI+: 193 480 ESI+: 240 481 ESI+: 285482 ESI+: 271 483 ESI+: 269 484 ESI+: 361 485 ESI+: 438, 440 486 ESI+:299 487 ESI+: 299 488 ESI+: 255 489 ESI+: 341 490 ESI+: 354 491 ESI+:304 492 ESI+: 347 493 ESI+: 354 494 ESI+: 299 495 ESI+: 273

TABLE 72 Rf Data 496 ESI+: 206 497 APCI/ESI+: 249 498 APCI/ESI+: 265 499ESI+: 171 500 ESI+: 347 501 ESI+: 321 502 ESI+: 323 503 ESI+: 333 504ESI+: 309 505 ESI+: 240 506 ESI+: 254 507 APCI/ESI+: 307 508 APCI/ESI+:324 509 ESI+: 340 510 APCI/ESI+: 390 511 ESI+: 318 512 ESI+: 290 513ESI+: 286 514 ESI+: 288 515 ESI+: 482 [M]+ 516 ESI+: 411 [M]+ 517 ESI+:494 [M]+ 518 ESI+: 270 519 ESI+: 270 520 ESI+: 374 521 ESI+: 287 522ESI+: 288 523 ESI+: 345 524 ESI+: 331 525 ESI+: 387 526 ESI+: 317 527ESI+: 287 528 ESI+: 364

TABLE 73 Rf Data 529 ESI+: 432 530 APCI/ESI+: 325 531 APCI/ESI+: 241 532APCI/ESI+: 255 533 APCI/ESI+: 241 534 APCI/ESI+: 255 535 APCI/ESI+: 317536 APCI/ESI+: 317 537 ESI+: 339 538 ESI+: 353 539 ESI+: 339 540 ESI+:255 541 ESI+: 418 542 ESI+: 353 543 ESI+: 448 544 ESI+: 339 545 ESI+:339 546 ESI+: 460 547 ESI+: 422 548 ESI+: 192 549 APCI/ESI+: 339 550APCI/ESI+: 407 551 APCI/ESI+: 418 552 APCI/ESI+: 451 553 APCI/ESI+: 404554 ESI+: 414 555 ESI+: 297 556 ESI+: 437 557 ESI+: 409 558 ESI+: 395559 ESI+: 409 560 ESI+: 423 561 APCI/ESI+: 451

TABLE 74 Rf Data 562 APCI/ESI+: 451 563 ESI+: 306 564 ESI+: 206 565ESI+: 340 566 ESI+: 337 567 ESI+: 590 568 EI: 222 569 ESI+: 342 570APCI/ESI+: 314 571 APCI/ESI+: 314 572 ESI+: 265 573 EI: 236+ 574 FAB+:273 575 ESI+: 316 576 FAB+: 280 577 ESI+: 374 578 ESI+: 303 579 ESI+:303 580 ESI+: 397 581 ESI+: 326 582 ESI+: 339 583 ESI+: 347 584 ESI+:305 585 ESI+: 297 586 ESI+: 173 587 ESI+: 277 588 ESI+: 327 589 EI: 256,258 590 ESI+: 261, 263 591 ESI+: 289, 291 592 EI: 142 593 APCI/ESI+: 362594 APCI/ESI+: 243, 245

TABLE 75 Rf Data 595 APCI/ESI+: 521, 523, 524 596 APCI/ESI+: 243, 245597 ESI+: 502 598 ESI+: 376 599 ESI+: 305 600 ESI+: 305 601 ESI+: 313602 ESI+: 429 603 ESI+: 401 604 ESI+: 415 605 ESI+: 399 606 ESI+: 328607 APCI/ESI+: 346 608 APCI/ESI+: 318 609 APCI/ESI+: 318 610 APCI/ESI+:310 611 APCI/ESI+: 349 612 ESI+: 312 613 APCI/ESI+: 249 614 ESI+: 258,260 615 ESI+: 489 616 ESI+: 515 617 ESI+: 419 618 ESI+: 447 619 ESI+:503 620 APCI/ESI+: 365 621 ESI+: 440 622 FAB+: 232 623 ESI+: 293 624ESI+: 194 625 ESI+: 410 626 ESI+: 424 627 ESI+: 279

TABLE 76 Rf Data 628 ESI+: 289 629 ESI+: 289 630 ESI+: 306 631 ESI+: 302632 ESI+: 318 633 ESI+: 331 634 ESI+: 532 635 ESI+: 504 636 ESI+: 441637 ESI+: 566 638 APCI/ESI+: 259 639 ESI+: 460 640 ESI+: 552 641 ESI+:582 642 ESI+: 454 643 APCI/ESI+: 552 644 ESI+: 490 645 APCI/ESI+: 538646 ESI+: 548 647 ESI+: 279 648 ESI+: 194 649 ESI+: 347 650 APCI/ESI+:319 651 APCI/ESI+: 360 652 APCI/ESI+: 390 653 APCI/ESI+: 249 654APCI/ESI+: 305 655 APCI/ESI+: 305 656 APCI/ESI+: 355 657 APCI/ESI+: 326658 APCI/ESI+: 348 659 APCI/ESI+: 346 660 APCI/ESI+: 305

TABLE 77 Rf Data 661 APCI/ESI+: 279 662 APCI/ESI+: 235 663 ESI+: 238 664ESI+: 300 665 ESI+: 340 666 ESI+: 354 669 ESI+: 349 670 ESI+: 236 671APCI/ESI+: 303 672 ESI+: 433 673 ESI+: 305 674 ESI+: 291 675 ESI+: 305676 ESI+: 319 677 ESI+: 144 678 ESI+: 454 679 ESI+: 328 680 ESI+: 330681 ESI+: 365 682 ESI+: 351 683 ESI+: 296 684 ESI+: 322 685 APCI/ESI+:376 686 APCI/ESI+: 335 687 ESI+: 346 688 APCI/ESI+: 376 689 APCI/ESI+:375 690 APCI/ESI+: 360 691 APCI/ESI+: 408 692 APCI/ESI+: 388 693APCI/ESI+: 402 694 APCI/ESI+: 386 695 APCI/ESI+: 379

TABLE 78 Rf Data 696 APCI/ESI+: 393 697 ESI+: 332 698 ESI+: 318 699ESI+: 362 700 ESI+: 348 701 ESI+: 342 702 ESI+: 365 703 ESI+: 337 704ESI+: 323 705 ESI+: 337 706 ESI+: 377 707 ESI+: 289 708 ESI+: 303 709APCI/ESI+: 362 710 ESI+: 264 711 ESI+: 264 712 ESI+: 151 713 ESI+: 386714 APCI/ESI+: 283 715 APCI/ESI+: 253 716 APCI/ESI+: 281 717 APCI/ESI+:345 718 APCI/ESI+: 422 719 APCI/ESI+: 374 720 APCI/ESI+: 388 721APCI/ESI+: 329 722 APCI/ESI+: 422 723 APCI/ESI+: 315 724 ESI+: 389 725ESI+: 417 726 APCI/ESI+: 297 727 APCI/ESI+: 323 728 APCI/ESI+: 309

TABLE 79 Rf Data 729 APCI/ESI+: 364 730 APCI/ESI+: 351 731 APCI/ESI+:345 732 APCI/ESI+: 345 733 APCI/ESI+: 316 734 APCI/ESI+: 316 735APCI/ESI+: 316 736 APCI/ESI+: 418 737 APCI/ESI+: 404 738 APCI/ESI+: 404739 APCI/ESI+: 423 740 APCI/ESI+: 423 741 APCI/ESI+: 423 742 APCI/ESI+:337 743 APCI/ESI+: 351 744 APCI/ESI+: 404 745 APCI/ESI+: 402 746APCI/ESI+: 432 747 APCI/ESI+: 336 748 APCI/ESI+: 364 749 ESI+: 200 750ESI+: 488 751 ESI+: 488 752 ESI+: 403 753 ESI+: 401 754 ESI+: 164 755ESI+: 335 756 ESI+: 321 757 ESI+: 454 758 ESI+: 452 759 ESI+: 452 760761 ESI+: 371

TABLE 80 Rf Data 762 APCI/ESI+: 375 763 APCI/ESI+: 389 764 APCI/ESI+:375 765 APCI/ESI+: 389 766 ESI+: 447 767 APCI/ESI+: 389 768 APCI/ESI+:403 769 ESI+: 309 770 ESI+: 365 771 ESI+: 391 772 ESI+: 493 773APCI/ESI+: 396 774 APCI/ESI+: 410 775 APCI/ESI+: 289 776 APCI/ESI+: 303777 APCI/ESI+: 315 778 APCI/ESI+: 317 779 APCI/ESI+: 317 780 APCI/ESI+:357 781 APCI/ESI+: 318 782 APCI/ESI+: 346 783 APCI/ESI+: 358 784APCI/ESI+: 360 785 ESI+: 373 786 ESI+: 381 787 ESI+: 408 788 ESI+: 368789 ESI+: 382 790 ESI+: 373 791 APCI/ESI+: 403 792 APCI/ESI+: 401 793ESI+: 271 794 ESI+: 285

TABLE 81 Rf Data 795 ESI+: 273 796 ESI+: 326 797 ESI+: 359 798 ESI+: 385799 ESI+: 289 800 ESI+: 317 801 ESI+: 373 802 APCI/ESI+: 351 803 ESI+:165 804 ESI+: 223 805 ESI+: 138 806 ESI+: 156 807 ESI+: 304 808 ESI+:183 809 ESI+: 241 810 ESI+: 379 811 ESI+: 474 812 ESI+: 446 813 ESI+:441 814 ESI+: 446 815 NMR-CDCl₃: 0.10(6H, s), 0.93(9H, s), 1.04-1.12(2H,m), 1.60- 1.70(3H, m), 2.38-2.49(1H, m), 2.63-2.73(2H, m), 3.60-3.66(2H,m), 4.00-4.19(4H, m), 4.75(2H, s), 6.37(1H, t, J = 7 Hz), 6.82- 6.87(1H,t, J = 7 Hz), 6.96(1H, t, J = 7 Hz). 816 ESI+: 446 817 ESI+: 289 818ESI+: 319 819 ESI+: 317 820 ESI+: 307 821 ESI+: 195 822 ESI+: 193 823ESI+: 168 824 ESI+: 323 825 ESI+: 407 826 ESI+: 332

TABLE 82 Rf Data 827 ESI+: 327 828 ESI+: 332 829 ESI+: 332 830 ESI+: 291831 ESI+: 281 832 ESI+: 349 833 ESI+: 337 834 ESI+: 321 835 ESI+: 333836 ESI+: 337 837 ESI+: 351 838 ESI+: 343 839 ESI+: 347 840 ESI+: 362841 ESI+: 223 842 ESI+: 305

Example 1

CDI (106 mg) was added to a mixture of1-(3-{2-[2-(morpholin-4-yl)pyrimidin-5-yl]ethyl}phenyl)methaneamine (97mg) and DMF (2 ml) at 0° C., followed by stirring at room temperaturefor 1 hour. The reaction mixture was concentrated under reducedpressure, and EtOAc and a saturated aqueous sodium hydrogen carbonatesolution were then added thereto. The organic layer was dried overNa₂SO₄ and concentrated under reduced pressure to obtain a reactionmixture. Guanidine hydrochloride (40 mg) and potassium tert-butoxide (45mg) were suspended in DMF (2 ml), and a solution of the reaction mixtureobtained immediately before in DMF (1 ml) was added thereto, followed bystirring at room temperature for 2 hours. The reaction mixture wasconcentrated under reduced pressure, water was then added thereto, andthe insoluble matter was collected by filtration. The solid thusobtained was purified by silica gel column chromatography (CHCl₃/MeOH),and L-tartaric acid (34 mg) was added to a mixture of the purifiedproduct (87 mg) in a mixed solvent (3 ml) of MeCN and water at 9:1,followed by stirring at room temperature for 1 hour. The insolublematter was collected by filtration to obtain1-carbamimidoyl-3-(3-{2-[2-(morpholin-4-yl)pyrimidin-5-yl]ethyl}benzyl)ureaL-tartrate (78 mg).

Example 2

CDI (248 mg) was added to a mixture of{3-[4-(2,6-dimethylpyridin-4-yl)piperazin-1-yl]-2-fluorophenyl}methanol(241 mg) and DMF (7 ml), followed by stirring at room temperature for 2hours. Guanidine carbonate (344 mg) was added to this mixture at roomtemperature, followed by stirring at room temperature overnight. Theorganic layer was evaporated under reduced pressure, water was added tothe residue, and the generated solid was collected by filtration.

The obtained solid was purified by basic silica gel columnchromatography (CHCl₃/MeOH). L-tartaric acid (99.3 mg) was added to amixture of the purified product thus obtained (265 mg) and EtOH (10 ml),followed by stirring at room temperature for 3 hours. The solid wascollected by filtration, washed with EtOH, and then dried under reducedpressure at 50° C. to obtain3-[4-(2,6-dimethylpyridin-4-yl)piperazin-1-yl]-2-fluorobenzylcarbamimidoylcarbamate (268 mg).

Example 3

1-[2-Fluoro-3-(hydroxymethyl)phenyl]-4-(pyridin-3-yl)piperidin-4-ol (187mg), DMF (5.5 ml), and CDI (201 mg) were mixed, followed by stirring atroom temperature for 2 hours. Guanidine carbonate (279 mg) was added tothe reaction mixture, followed by stirring at room temperatureovernight. Water was added to the reaction mixture, followed byice-cooling and stirring for 30 minutes, and the generated solid wascollected by filtration, washed with water, and then dried at 50° C.under reduced pressure. The obtained solid was purified by silica gelcolumn chromatography (CHCl₃/MeOH) to obtain2-fluoro-3-[4-hydroxy-4-(pyridin-3-yl)piperidin-1-yl]benzylcarbamimidoylcarbamate (160 mg).

Example 23

CDI (110 mg) was added to a mixture of1-{4-[({5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}oxy)methyl]piperidin-1-yl}propan-1-one(124 mg) and DMF (3 ml), followed by stirring at room temperature for 3hours. Guanidine carbonate (220 mg) was added to the reaction mixture,followed by stirring at room temperature overnight. The organic layerwas evaporated under reduced pressure, water was added to the residue,and the generated solid was collected by filtration.

The obtained solid was purified by silica gel column chromatography(CHCl₃/MeOH). A 4M hydrogen chloride/dioxane solution (0.1 ml) was addedto a mixture of the purified product thus obtained (135.1 mg) and EtOH(2 ml), followed by stirring at room temperature for 1 hour andconcentrating under reduced pressure. The obtained solid was washed withether and then collected by filtration to obtain2-fluoro-3-{2-[(1-propionylpiperidin-4-yl)methoxy]pyrimidin-5-yl}benzylcarbamimidoylcarbamate dihydrochloride (140 mg) as a colorless solid.

Example 112

CDI (225 mg) was added to a mixture of1-(4-{5-[3-(hydroxymethyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)-2-methoxyethanone(216 mg) and DMF (6 ml), followed by stirring at room temperature for 2hours. Then, guanidine carbonate (220 mg) was added to the mixture,followed by stirring at room temperature for 2 hours. Water was added tothe reaction mixture, followed by extraction with CHCl₃. The organiclayer was dried over Na₂SO₄ and evaporated under reduced pressure. Amixture obtained by dissolving L-tartaric acid (59 mg) in a mixedsolvent (1 ml) of MeCN and water at 9:1 was added to a mixture of theobtained residue (166.9 mg) in a mixed solvent (4 ml) of MeCN and waterat 9:1, followed by stirring at room temperature. The precipitated solidwas collected by filtration to obtain3-{2-[4-(methoxyacetyl)piperazin-1-yl]pyrimidin-5-yl}benzylcarbamimidoylcarbamate L-tartrate (177 mg) as a colorless solid.

Example 316

A 4M hydrogen chloride/EtOH solution (1.5 ml) was added to a mixture of2-fluoro-3-{4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]piperazin-1-yl}benzylcarbamimidoylcarbamate(285 mg) and EtOH (5 ml), followed by stirring at room temperature. Theprecipitated yellow solid was collected by filtration and washed withEtOH. The obtained solid was dried at 40° C. under reduced pressure toobtain2-fluoro-3-{4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]piperazin-1-yl}benzylcarbamimidoylcarbamate trihydrochloride (330 mg).

Example 317

Ethyl({1-[5-(3-{[(carbamimidoylcarbamoyl)oxy]methyl}phenyl)pyrimidin-2-yl]piperidin-4-yl}oxy)acetate(45 mg) was mixed with ethanol, and L-tartaric acid (15 mg) was addedthereto, followed by stirring at room temperature for 1 hour. Thereaction mixture was concentrated under reduced pressure, and thendiethyl ether was added thereto. The precipitated solid was collected byfiltration to obtain ethyl({1-[5-(3-{[(carbamimidoylcarbamoyl)oxy]methyl}phenyl)pyrimidin-2-yl]piperidin-4-yl}oxy)acetateL-tartrate (28 mg).

Example 318

A 1M aqueous NaOH solution was added to a mixture of methyl4-{4-[5-(3-{[(carbamimidoylcarbamoyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}-3-chlorobenzoate(208 mg), THF (2 ml), and EtOH (2 ml), followed by stirring at roomtemperature for 2 hours. The reaction mixture was neutralized with 1Mhydrochloric acid, and the precipitated solid was collected byfiltration. A 4M hydrogen chloride/dioxane solution (1 ml) was added toa mixture of the obtained solid and dioxane (3 ml), followed by stirringat room temperature overnight. The insoluble matter was collected byfiltration to obtain4-{4-[5-(3-{[(carbamimidoylcarbamoyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}-3-chlorobenzoicacid dihydrochloride (112 mg).

Example 319

Sodium hydride (50% suspended in mineral oil, 45 mg) was added to amixture of {3-[2-(morpholin-4-yl)pyrimidin-5-yl]phenyl}methanol (230 mg)and DMF (6 ml) under ice-cooling. After stirring at the same temperaturefor 30 minutes, CDI (275 mg) was added thereto. The reaction mixture wasstirred at room temperature for 2 hours, and guanidine carbonate (460mg) and DBU (388 mg) were then added thereto, followed by stirring atroom temperature overnight. The solvent was evaporated under reducedpressure, water was added to the obtained residue, and the generatedinsoluble matter was collected by filtration. The obtained solid waspurified by basic silica gel column chromatography (CHCl₃/MeOH).L-tartaric acid (23 mg) was added to a mixture of the purified productthus obtained (54 mg), MeCN, and water, followed by stirring at roomtemperature for 30 minutes. The generated insoluble matter was collectedby filtration, and washed with MeCN to obtain3-[2-(morpholin-4-yl)pyrimidin-5-yl]benzylcarbamimidoylcarbamateL-tartrate (66 mg).

Example 328

A 1M aqueous NaOH solution (1.14 ml) was added to a mixture of5-[4-(3-{[(carbamimidoylcarbamoyl)oxy]methyl}-2-fluorophenyl)piperazin-1-yl]pyridine-2-carboxylatemethyl ester (326 mg), THF (9 ml), and MeOH (3 ml), followed by stirringat room temperature overnight. 1M hydrochloric acid (1.14 ml) was addedto the reaction mixture, followed by stirring at room temperature for 1hour. The generated solid was collected by filtration, washed withwater, and then dried at 50° C. under reduced pressure to obtain5-[4-(3-{[(carbamimidoylcarbamoyl)oxy]methyl}-2-fluorophenyl)piperazin-1-yl]pyridine-2-carboxylicacid (293 mg).

Example 344

A 1M aqueous NaOH solution was added to a mixture of ethyl4-{1-[5-(3-{[(carbamimidoylcarbamoyl)oxy]methyl}-2-fluorophenyl)pyrimidin-2-yl]piperidin-4-yl}butanoate(256 mg), THF (3.3 ml), and EtOH (3.3 ml), followed by stirring at roomtemperature overnight. The insoluble matter was removed by filtration,the solvent was evaporated under reduced pressure, and to the residuewere then added water and 1M hydrochloric acid (1.052 ml) at 0° C.,followed by stirring at 0° C. for 30 minutes. The solid was collected byfiltration, washed with water, and then dried at 50° C. under reducedpressure. To the reaction mixture was added MeCN (8 ml), and a mixtureof L-tartaric acid (76.6 mg), MeCN (4 ml), and water (0.2 ml) was addedthereto, followed by stirring at room temperature overnight. The solidwas collected by filtration, washed with MeCN, and then dried at 50° C.under reduced pressure to obtain4-{1-[5-(3-{[(carbamimidoylcarbamoyl)oxy]methyl}-2-fluorophenyl)pyrimidin-2-yl]piperidin-4-yl}butanoicacid L-tartrate (276 mg).

Example 345

To a mixture of1-[5-(3-{[(carbamimidoylcarbamoyl)oxy]methyl}-2-fluorophenyl)pyrimidin-2-yl]piperidin-4-ylbenzoic acid (252 mg) and MeOH was added a 1M aqueous NaOH solution (1ml), followed by stirring at room temperature for 3 hours. To thereaction mixture was added a 1M aqueous HCl solution (1 ml), and thenthe reaction mixture was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (CHCl₃/MeOH) asit was.

To the purified product thus obtained was added EtOH, and 4M hydrogenchloride/dioxane (1 ml) was added thereto, followed by stirring at roomtemperature for 1 hour. The reaction mixture was concentrated underreduced pressure, and then diethyl ether were added thereto. Theprecipitated solid was collected by filtration to obtain2-fluoro-3-[2-(4-hydroxypiperidin-1-yl)pyrimidin-5-yl]benzylcarbamimidoylcarbamate dihydrochloride (110 mg).

Example 347

To a mixture of1-(3-{2-[3-(methoxymethyl)pyrrolidin-1-yl]pyrimidin-5-yl}phenyl)methanamine(158 mg) and DMF (3 ml) was added CDI (110 mg), followed by stirring atroom temperature for 1 hour.

The reaction mixture was concentrated under reduced pressure, EtOAc anda saturated aqueous sodium hydrogen carbonate solution were then addedthereto, and the organic layer was dried over Na₂SO₄ and concentratedunder reduced pressure to obtain a reaction mixture. Guanidinehydrochloride and sodium hydride were suspended in DMF (2 ml), and asolution of the reaction mixture obtained immediately before in DMF (1ml) was added thereto, followed by stirring at room temperature for 1hour. The reaction mixture was concentrated under reduced pressure,water was added thereto, and the insoluble matter was collected byfiltration. The obtained solid was purified by silica gel columnchromatography (CHCl₃/MeOH). To the purified product thus obtained (73mg) was added a mixed solvent (3.3 ml) of MeCN and water at 9:1, andfurther, L-tartaric acid (29 mg) was added thereto, followed by stirringat room temperature for 1 hour. The insoluble matter was collected byfiltration to obtain1-carbamimidoyl-3-(3-{2-[3-(methoxymethyl)pyrrolidin-1-yl]pyrimidin-5-yl}benzyl)ureaL-tartrate (65 mg).

Example 397

Methyl4-(4-{5-[3-(aminomethyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)-3-chlorobenzoate(207 mg) was mixed with DMF (5 ml), and CDI (154 mg) was added theretoat 0° C., followed by stirring at room temperature for 2 hours. Thereaction mixture was concentrated under reduced pressure, and EtOAc anda saturated aqueous sodium hydrogen carbonate solution were then addedthereto. The organic layer was dried over Na₂SO₄ and concentrated underreduced pressure. The obtained residue was mixed with DMF (5 ml), andguanidine hydrochloride (50 mg) and DBU(204 mg) were added thereto,followed by stirring at 70° C. for 5 hours. The reaction mixture wasconcentrated under reduced pressure, water was then added thereto, andthe insoluble matter was collected by filtration. The obtained solid waspurified by basic silica gel column chromatography (CHCl₃/MeOH) toobtain methyl4-{4-[5-(3-{[(carbamimidoylcarbamoyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}-3-chlorobenzoate(208 mg).

Example 398

Ethyl1-{5-[3-(aminomethyl)phenyl]pyrimidin-2-yl}piperidine-4-carboxylate (303mg) was mixed with DMF (5 ml), and CDI (188 mg) was added thereto,followed by stirring at room temperature for 1 hour. The reactionmixture was concentrated under reduced pressure, and EtOAc and asaturated aqueous sodium hydrogen carbonate solution were then addedthereto. The organic layer was dried over Na₂SO₄ and concentrated underreduced pressure. Guanidine hydrochloride (170 mg) and sodium hydride(55% suspended in oil) (77 mg) were suspended in DMF (2 ml), and asolution of the reaction mixture obtained immediately before in DMF (1ml) was added thereto, followed by stirring at room temperature for 1hour. The reaction mixture was concentrated under reduced pressure,water was then added thereto, and the insoluble matter was collected byfiltration. The obtained solid was purified by silica gel columnchromatography (CHCl₃/MeOH) to obtain ethyl1-[5-(3-{[(carbamimidoylcarbamoyl)amino]methyl}phenyl)pyrimidin-2-yl]piperidine-4-carboxylate(74 mg).

Example 546

tert-Butyl [3-(2-chloropyrimidin-5-yl)benzyl]carbamate (16 mg) and1-methyl-2-pyrrolidinone (0.2 ml) were mixed, and ethyl4-aminopiperidine-1-carboxylate (8 mg) and sodium carbonate (20 mg) wereadded thereto, followed by stirring at 90° C. overnight. The reactionmixture was cooled to room temperature and then filtered, and thefiltrate was purified by preparative liquid chromatography (MeOH/0.1%aqueous formic acid solution). To the purified product thus obtainedwere added MeOH (0.5 ml) and a 4M hydrogen chloride/EtOAc solution (0.5ml), followed by shaking for 2 hours. The reaction mixture wasconcentrated, and to the obtained residue were added DMF (0.2 ml) andCDI (4 mg), followed by stirring at room temperature for 2 hours. To thereaction mixture was added guanidine carbonate (9 mg), followed bystirring at 90° C. overnight. The reaction mixture was cooled to roomtemperature, and the insoluble matter was then filtered. The filtratewas purified by preparative liquid chromatography (MeOH/0.1% aqueousformic acid solution) to obtain ethyl4-{[5-(3-{[(carbamimidoylcarbamoyl)amino]methyl}phenyl)pyrimidin-2-yl]amino}piperidine-1-carboxylate(1.9 mg).

Example 567

4-{1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine(70 mg) and TEA (73 mg) were mixed with dichloromethane (2 ml), andacetyl chloride (22 mg) was added thereto, followed by stirring at roomtemperature for 1 hour. To the reaction mixture were added CHCl₃ and a1M aqueous NaOH solution, the organic layer was dried over Na₂SO₄, andthe organic layer was concentrated under reduced pressure. The obtainedresidue was mixed with THF (2 ml), and a 1M TBAF/THF solution (0.3 ml)was added thereto, followed by stirring at room temperature for 1 hour.To the reaction mixture were added CHCl₃ and a saturated aqueousammonium chloride solution, and the organic layer was dried over Na₂SO₄.The reaction mixture was concentrated under reduced pressure. Theobtained residue was purified by silica gel column chromatography(CHCl₃/MeOH). The purified product thus obtained was mixed with DMF, andCDI (65 mg) was added thereto, followed by stirring at room temperaturefor 3 hours. To the reaction mixture was added guanidine carbonate (140mg), followed by stirring at room temperature for 1 hour. The reactionmixture was concentrated under reduced pressure, water was addedthereto, and the insoluble matter was collected by filtration. Theobtained solid was purified by basic silica gel column chromatography(CHCl₃/MeOH). The purified product thus obtained was mixed with EtOH (1ml), and L-tartaric acid (16 mg) was added thereto, followed by stirringat room temperature for 1 hour. The precipitated solid was collected byfiltration to obtain3-[3-(1-acetylpiperidin-4-yl)azetidin-1-yl]-2-fluorobenzylcarbamimidoylcarbamate L-tartrate (49 mg).

Example 568

3-[4-(6-tert-Butoxypyridin-3-yl)piperazin-1-yl]-2-fluorobenzylcarbamimidoylcarbamate (132 mg) was dissolved in dichloromethane (3.4ml), and TFA (508 mg) was added thereto, followed by stirring at roomtemperature for 4 hours. The reaction mixture was concentrated underreduced pressure, the residue was mixed with HC1₃/MeOH, and basic silicagel was added thereto, followed by concentrating under reduced pressure.The residue was purified by basic silica gel column chromatography(CHC1₃/ MeOH). The purified product thus obtained was mixed with EtOH (5ml), and L-tartaric acid (41.0 mg) were added thereto, followed bystirring at 80° C. for 1 hour, and then stirring at room temperature for1 hour. The solid was collected by filtration, washed with EtOH, andthen dried at 50° C. under reduced pressure to obtain2-fluoro-3[4-(6-oxo-1,6-dihydropyridin-3-yl)piperazin-l-yl]benzylcarbamimidoylcarbamate L-tartrate (125 mg).

Example 588

Methyl5-{4-[({1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)methyl]piperidin-1-yl}pyridine-2-carboxylate(69 mg), DMF (2 ml), and CDI (60 mg) were mixed, followed by stirring atroom temperature for 3 hours. To the reaction mixture was addedguanidine carbonate (120 mg), followed by stirring at room temperaturefor 1 hour. The reaction mixture was concentrated under reducedpressure, and water and CHCl₃ were added thereto. The organic layer wasdried over Na₂SO₄ and concentrated under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (CHCl₃/MeOH).

The purified product thus obtained was mixed with methanol (1 ml) andTHF (2 ml), and a 1M aqueous NaOH solution (0.2 ml) was added thereto,followed by stirring at room temperature overnight. To the reactionmixture was added 1M hydrochloric acid (0.2 ml), followed byconcentrating under reduced pressure. To the residue was added methanol,the insoluble matter was separated by filtration, and the filtrate wasconcentrated under reduced pressure. To the residue was added methanol,the insoluble matter was separated by filtration, and the filtrate wasconcentrated under reduced pressure. To the residue were added a smallamount of methanol and then diethyl ether. The precipitated solid wascollected by filtration to obtain5-[4-({[1-(3-{[(carbamimidoylcarbamoyl)oxy]methyl}-2-fluorophenyl)azetidin-3-yl]oxy}methyl)piperidin-1-yl]pyridine-2-carboxylicacid (23 mg).

Example 615

To a mixture of(3-{3-[(6-tert-butoxypyridin-3-yl)oxy]azetidin-1-yl}-2-fluorophenyl)methanol(120 mg) and DMF (2 ml) was added CDI (130 mg), followed by stirring atroom temperature for 3 hours. To the reaction mixture was addedguanidine carbonate (260 mg), followed by stirring at room temperaturefor 1 hour. The reaction mixture was concentrated under reducedpressure, water and CHCl₃ were added thereto, and the organic layer wasdried over anhydrous sodium sulfate. After concentrating under reducedpressure, the obtained residue was purified by silica gel columnchromatography (CHCl₃/MeOH). The purified product thus obtained wasmixed with dichloromethane (2 ml), and TFA (0.5 ml) was added thereto,followed by stirring at room temperature overnight. The reactionsolution was concentrated under reduced pressure, and a saturatedaqueous sodium hydrogen carbonate solution and CHCl₃ were then addedthereto. The organic layer was dried over Na₂SO₄ and then concentratedunder reduced pressure. The obtained residue was mixed with a mixedsolution of MeCN and H₂O at 95:5, and L-tartaric acid (41 mg) was addedthereto, followed by stirring at room temperature for 1 hour. The solidwas collected by filtration to obtain2-fluoro-3-({3-[(6-oxo-1,6-dihydropyridin-3-yl)oxy]azetidin-1-yl}benzylcarbamimidoylcarbamate L-tartrate (118 mg).

Example 619

2-Fluoro-3-[2-(morpholin-4-yl)pyrimidin-5-yl]benzylcarbamimidoylcarbamate hydrochloride (54 mg), CHCl₃ (8 ml), and MeOH (3ml) were mixed, and a saturated aqueous sodium hydrogen carbonatesolution was added thereto, followed by stirring for 10 minutes. Theorganic layer was dried over Na₂SO₄, and the solvent was evaporatedunder reduced pressure. The solid residue was washed with EtOAc andfiltered to obtain a colorless solid.

The obtained solid was mixed with a mixed solvent of EtOH (0.54 ml) andwater (0.54 ml), and a 1M aqueous phosphoric acid solution, followed bystirring for 1 hour. The solid was collected by filtration, and washedwith a mixture (1:1) of EtOH and water. The obtained solid was dried at50° C. under reduced pressure to obtain2-fluoro-3-[2-(morpholin-4-yl)pyrimidin-5-yl]benzylcarbamimidoylcarbamate phosphate (45 mg) as a colorless solid.

The compounds of Examples shown in the tables below were prepared usingthe respective corresponding starting materials in the same manner asthe methods of Examples above. The structures, the preparation methods,and the physicochemical data for the compounds of Examples are shown inthe tables below.

TABLE 83 Ex Syn Structure  1  1

 2  2

 3  3

 4 23

 5 23

 6 23

 7 23

 8 23

 9 23

10 23

11 23

12 23

13 23

14 23

15 23

16 23

17 23

18 23

TABLE 84 Ex Syn Structure 19 23

20 23

21 23

22 23

23 23

24 23

25 23

26 23

27 23

28 23

29 23

30 23

31 23

32 23

33 23

34 23

35 23

36 23

TABLE 85 Ex Syn Structure 37 23

38 23

39 23

40 23

41 23

42 23

43 23

44 23

45 23

46 23

47 23

48 23

49 23

50 23

51 23

52 23

53 23

54 23

TABLE 86 Ex Syn Structure 55 23

56 23

57 23

58 23

59 23

60 23

61 23

62 23

63 23

64 23

65 23

66 23

67 23

68 23

69 23

70 23

71 23

72 23

TABLE 87 Ex Syn Structure 73 23

74 23

75 23

76 23

77 23

78 23

79 23

80 23

81 23

82 23

83 23

84 23

85 23

86 23

87 23

88 23

89 23

90 23

TABLE 88 Ex Syn Structure 91 23

92 23

93 23

94 23

95 23

96 23

97 23

98 23

99 112

100 112

101 112

102 112

103 112

104 112

105 112

106 112

107 112

108 112

TABLE 89 Ex Syn Structure 109 112

110 112

111 112

112 112

113 112

114 112

115 112

116 112

117 112

118 112

119 112

120 112

121 112

122 112

123 112

124 112

TABLE 90 Ex Syn Structure 125 112

126 112

127 112

128 112

129 112

130 112

131 112

132 112

133 112

134 112

135 112

136 112

137 112

138 112

139 112

140 112

141 112

142 112

TABLE 91 Ex Syn Structure 143 112

144 112

145 112

146 112

147 112

148 112

149 112

150 112

151 112

152 112

153 112

154 112

155 112

156 112

157 112

158 112

159 112

160 112

TABLE 92 Ex Syn Structure 161 112

162 112

163 112

164 112

165 112

166 112

167 112

168 112

169 112

170 112

171 112

172 112

173 112

174 112

175 112

176 112

177 112

178 112

TABLE 93 Ex Syn Structure 179 112

180 112

181 112

182 112

183 112

184 112

185 112

186 112

187 112

188 112

189 112

190 112

191 112

192 112

193 112

194 112

TABLE 94 Ex Syn Structure 195 112

196 112

197 112

198 112

199 112

200 112

201 112

202 112

203 112

204 112

205 112

206 112

207 112

208 112

209 112

210 112

211 112

212 112

TABLE 95 Ex Syn Structure 213 112

214 112

215 112

216 112

217 112

218 112

219 112

220 112

221 112

222 112

223 112

224 112

225 112

226 112

227 112

228 112

229 112

230 112

TABLE 96 Ex Syn Structure 231 112

232 112

233 112

234 112

235 112

236 112

237 112

238 112

239 112

240 112

241 112

242 112

243 112

244 112

245 112

246 112

247 112

248 112

TABLE 97 Ex Syn Structure 249 112

250 112

251 112

252 112

253 112

254 112

255 112

256 112

257 112

258 112

259 112

260 112

261 112

262 112

263 112

264 112

265 112

266 112

TABLE 98 Ex Syn Structure 267 112

268 112

269 112

270 112

271 112

272 112

273 112

274 112

275 112

276 112

277 112

278 112

279 112

280 112

281 112

282 112

283 112

284 112

TABLE 99 Ex Syn Structure 285 112

286 112

287 112

288 112

289 112

290 112

291 112

292 112

293 112

294 112

295 112

296 112

297 112

298 112

299 112

300 112

TABLE 100 Ex Syn Structure 301 112

302 112

303 112

304 112

305 112

306 112

307 112

308 112

309 112

310 112

311 112

312 112

313 112

314 112

315 112

316 316

TABLE 101 Ex Syn Structure 317 317

318 318

319 319

320 319

321 319

322 319

323 319

324 319

325 328

326 328

327 328

328 328

329 318

330 318

331 318

332 318

TABLE 102 Ex Syn Structure 333 318

334 318

335 318

336 318

337 318

338 318

339 318

340 344

341 344

342 318

343 344

344 344

345 345

346 347

347 347

348 347

349 347

350 347

TABLE 103 Ex Syn Structure 351 347

352 347

353 347

354 347

355 347

356 347

357 347

358 347

359 347

360 347

361 347

362 347

363 347

364 347

365 347

366 347

TABLE 104 Ex Syn Structure 367 347

368 347

369 347

370 347

371 347

372 318

373 23

374 112

375 3

376 3

377 3

378 3

379 3

380 3

381 3

382 3

383 3

384 3

TABLE 105 Ex Syn Structure 385 3

386 3

387 3

388 3

389 3

390 3

391 3

392 3

393 3

394 3

395 3

396 3

397 397

398 398

399 546

400 546

TABLE 106 Ex Syn Structure 401 546

402 546

403 546

404 546

405 546

406 546

407 546

408 546

409 546

410 546

411 546

412 546

413 546

414 546

TABLE 107 Ex Syn Structure 415 546

416 546

417 546

418 546

419 546

420 546

421 546

422 546

423 546

424 546

425 546

426 546

TABLE 108 Ex Syn Structure 427 546

428 546

429 546

430 546

431 546

432 546

433 546

434 546

435 546

436 546

437 546

438 546

TABLE 109 Ex Syn Structure 439 546

440 546

441 546

442 546

443 546

444 546

445 546

446 546

447 546

448 546

449 546

450 546

TABLE 110 Ex Syn Structure 451 546

452 546

453 546

454 546

455 546

456 546

457 546

458 546

459 546

460 546

461 546

462 546

TABLE 111 Ex Syn Structure 463 546

464 546

465 546

466 546

467 546

468 546

469 546

470 546

471 546

472 546

473 546

474 546

TABLE 112 Ex Syn Structure 475 546

476 546

477 546

478 546

479 546

480 546

481 546

482 546

483 546

484 546

TABLE 113 Ex Syn Structure 485 546

486 546

487 546

488 546

489 546

490 546

491 546

492 546

493 546

494 546

TABLE 114 Ex Syn Structure 495 546

496 546

497 546

498 546

499 546

500 546

501 546

502 546

503 546

504 546

505 546

506 546

TABLE 115 Ex Syn Structure 507 546

508 546

509 546

510 546

511 546

512 546

513 546

514 546

515 546

516 546

517 546

518 546

519 546

520 546

TABLE 116 Ex Syn Structure 521 546

522 546

523 546

524 546

525 546

526 546

527 546

528 546

529 546

530 546

531 546

532 546

TABLE 117 Ex Syn Structure 533 546

534 546

535 546

536 546

537 546

538 546

539 546

540 546

541 546

542 546

TABLE 118 Ex Syn Structure 543 546

544 546

545 546

546 546

547 546

548 546

549 546

550 546

551 112

552 112

TABLE 119 Ex Syn Structure 553 112

554 112

555 112

556 112

557 112

558 112

559 567

560 112

561 112

562 112

563 112

564 112

565 112

566 112

567 567

TABLE 120 Ex Data 1 ESI+: 384 2 ESI+: 401 3 ESI+: 388 4 ESI+: 417 5ESI+: 418 6 ESI+: 426 7 ESI+: 430 8 ESI+: 443 9 ESI+: 431 10 ESI+: 487NMR-DMSO-d₆: 1.37-1.50 (2H, m), 1.83-1.94 (2H, m), 3.21-3.50 (14H, m),4.06-4.18 (2H, m), 5.29 (2H, s), 7.08-7.22 (3H, m), 8.49 (2H, s) 11ESI+: 445 NMR-DMSO-d₆: 1.06-1.34 (2H, m), 1.71-1.85 (2H, m), 2.00 (3H,s), 2.01-2.14 (1H, m), 2.50-2.60 (1H, m), 3.00-3.11 (1H, m), 3.80- 3.90(1H, m), 4.25 (2H, d, J = 6.4 Hz), 4.36-4.46 (1H, m), 5.37 (2H, s), 7.39(1H, t, J = 7.6 Hz), 7.55-7.63 (1H, m), 7.64-7.72 (1H, m), 8.78-8.83(2H, m) 12 ESI+: 475 13 ESI+: 390 14 ESI+: 390 15 ESI+: 440 16 ESI+: 43017 ESI+: 430 18 ESI+: 430 19 ESI+: 401 20 ESI+: 401 21 ESI+: 401 22ESI+: 507 23 ESI+: 459 NMR-DMSO-d₆: 0.99 (3H, t, J = 7.4 Hz), 1.03-1.32(2H, m), 1.71- 1.87 (2H, m), 2.00-2.13 (1H, m), 2.32 (2H, q, J = 7.4Hz), 2.50- 2.62 (1H, m), 2.96-3.08 (1H, m), 3.84-3.95 (1H, m), 4.24 (2H,d, J = 6.25 Hz), 4.38-4.48 (1H, m), 5.37 (2H, s), 7.39 (1H, t, J = 7.7Hz), 7.55-7.62 (1H, m), 7.64-7.71 (1H, m), 8.77-8.83 (2H, m) 24 ESI+:473

TABLE 121 Ex Data 25 ESI+: 503 26 ESI+: 489 27 ESI+: 489 28 ESI+: 508 29ESI+: 508 30 ESI+: 508 31 ESI+: 474 32 ESI+: 461 33 ESI+: 507 34 ESI+:481 35 ESI+: 495 36 ESI+: 474 37 ESI+: 502 38 ESI+: 486 39 ESI+: 488 40ESI+: 488 41 ESI+: 362 42 ESI+: 362 43 ESI+: 354 44 ESI+: 441 45 ESI+:369 46 ESI+: 416 NMR-DMSO-d₆: 2.06 (3H, s), 3.54-3.56 (4H, m), 3.77-3.86(4H, m), 5.35 (2H, s), 7.33-7.37 (1H, m), 7.49-7.54 (1H, m), 7.60-7.64(1H, m), 8.61 (2H, s) 47 ESI+: 404 48 ESI+: 416 49 ESI+: 412 50 ESI+:355 51 ESI+: 355 NMR-DMSO-d₆: 3.36-3.38 (4H, m), 3.59-3.62 (4H, m), 5.20(2H, s), 6.91 (1H, d, J = 7.6 Hz), 7.06-7.08 (1H, m), 7.13 (1H, s),7.28- 7.32 (1H, m), 7.87 (1H, dd, J = 9.0, 5.4 Hz), 8.15-8.18 (1H, m),8.22 (1H, d, J = 5.3 Hz), 8.53 (1H, d, J = 2.7 Hz)

TABLE 122 Ex Data 52 ESI+: 372 NMR-DMSO-d₆: 1.88-2.01 (4H, m), 2.83-2.89(2H, m), 3.04-3.12 (1H, m), 3.49-3.52 (2H, m), 5.28 (2H, s), 7.08-7.12(1H, m), 7.16-7.18 (2H, m), 8.08-8.09 (2H, m), 8.87-8.88 (2H, m) 53ESI+: 373 NMR-DMSO-d₆: 3.17-3.19 (4H, m), 3.85-3.88 (4H, m), 5.29 (2H,s), 7.11-7.20 (3H, m), 7.27-7.28 (2H, m), 8.27-8.30 (2H, m) 54 ESI+: 45955 ESI+: 416 56 ESI+: 430 57 ESI+: 402 58 ESI+: 372 59 ESI+: 449 60ESI+: 391, 393 61 ESI+: 397 62 ESI+: 421 63 ESI+: 375 NMR-DMSO-d₆: 3.27(3H, s), 3.89-3.95 (2H, m), 4.27-4.39 (3H, m), 5.35 (2H, s), 7.31-7.38(1H, m), 7.48-7.55 (1H, m), 7.57-7.64 (1H, m), 8.53-8.58 (2H, m) 64ESI+: 403 NMR-DMSO-d₆: 1.17 (3H, s), 1.41-1.60 (4H, m), 3.41-3.54 (2H,m), 4.20-4.29 (2H, m), 5.35 (2H, s), 7.31-7.37 (1H, m), 7.46-7.54 (1H,m), 7.57-7.64 (1H, m), 8.53-8.58 (2H, m) 65 ESI+: 389 66 ESI+: 403 67ESI+: 403 68 ESI+: 445 69 ESI+: 493 70 ESI+: 494 71 ESI+: 473 72 ESI+:499 73 ESI+: 487

TABLE 123 Ex Data 74 ESI+: 471 NMR-DMSO-d₆: 0.61-0.78 (4H, m), 1.00-1.35(2H, m), 1.66-1.91 (2H, m), 1.92-2.02 (1H, m), 2.02-2.17 (1H, m),2.53-2.69 (1H, m), 3.00-3.21 (1H, m), 4.15-4.48 (4H, m), 5.37 (2H, s),7.33- 7.43 (1H, m), 7.52-7.63 (1H, m), 7.63-7.72 (1H, m), 8.74- 8.84(2H, m) 75 ESI+: 483 76 ESI+: 490 77 ESI+: 464 78 ESI+: 478 79 ESI+: 41780 ESI+: 427 81 ESI+: 375 NMR-DMSO-d₆: 3.67-3.71 (4H, m), 3.74-3.78 (4H,m), 5.35 (2H, s), 7.34 (1H, dd, J = 7.7, 7.7 Hz), 7.49-7.53 (1H, m),7.59-7.63 (1H, m), 8.59-8.60 (2H, m) 82 ESI+: 375 83 ESI+: 361 84 ESI+:509 85 ESI+: 510 86 ESI+: 362 87 ESI+: 402 88 ESI+: 403 89 ESI+: 419 90ESI+: 402 91 ESI+: 473 92 ESI+: 428 93 ESI+: 458 94 ESI+: 396 95 ESI+:387 96 ESI+: 374 97 ESI+: 387 98 ESI+: 387 99 ESI+: 465 100 ESI+: 419101 ESI+: 457

TABLE 124 Ex Data 102 ESI+: 441 103 ESI+: 432 104 ESI+: 426 105 ESI+:444 NMR-DMSO-d₆: 1.09-1.18 (1H, m), 1.22-1.32 (1H, m), 1.78 (2H, t, J =16 Hz), 2.00 (3H, s), 2.01-2.11 (1H, m), 2.52-2.59 (1H, m), 3.00-3.09(1H, m), 3.85 (1H, d, J = 14 Hz), 4.09 (2H, s), 4.24 (2H, d, J = 6 Hz),4.40-4.42 (3H, m), 7.31 (1H, t, J = 7 Hz), 7.41 (1H, t, J = 7 Hz), 7.52(1H, t, J = 7 Hz), 8.78-8.79 (2H, m) 106 ESI+: 470 NMR-DMSO-d₆:0.62-0.75 (4H, m), 1.08-1.34 (2H, m), 1.72-1.89 (2H, m), 1.93-2.01 (1H,m), 2.05-2.15 (1H, m), 2.55-2.66 (1H, m), 3.05-3.17 (1H, m), 4.09 (2H,s), 4.20-4.45 (6H, m), 7.31 (1H, t, J = 7 Hz), 7.41 (1H, t, J = 7 Hz),7.52 (1H, t, J = 7 Hz), 8.78-8.79 (2H, m) 107 ESI+: 413 108 ESI+: 415109 ESI+: 459 110 ESI+: 487 111 ESI+: 458 112 FAB+: 428 113 ESI+: 503NMR-DMSO-d₆: 3.10-3.19 (8H, m), 3.25 (3H, s), 3.42-3.55 (4H, m),3.73-3.80 (2H, m), 4.12-4.21 (3H, m), 4.35-4.43 (1H, m), 5.04 (2H, s),6.98-7.15 (3H, m), 8.25 (2H, s) 114 ESI+: 459 115 ESI+: 446 116 ESI+:443 117 ESI+: 487 118 ESI+: 461 119 ESI+: 461 120 ESI+: 458 121 ESI+:479 122 ESI+: 473 123 ESI+: 500 124 ESI+: 441

TABLE 125 Ex Data 125 ESI+: 447 126 ESI+: 404 127 ESI+: 368 128 ESI+:382 129 ESI+: 408 130 ESI+: 338 131 ESI+: 297 132 ESI+: 474 133 ESI+:404 134 ESI+: 366 135 ESI+: 394 136 ESI+: 334 137 ESI+: 449 138 ESI+:436 139 ESI+: 411 140 ESI+: 431 141 ESI+: 433 142 ESI+: 450 143 ESI+:464 144 ESI+: 450 NMR-DMSO-d₆: 1.11 (3H, t, J = 7 Hz), 1.31-1.51 (4H,m), 1.59-1.73 (2H, m), 1.77-1.88 (2H, m), 2.59-2.70 (1H, m), 2.88- 3.04(4H, m), 3.39 (2H, q, J = 7 Hz), 3.47-3.53 (1H, m), 3.55-3.70 (4H, m),4.21 (2H, s), 5.05 (2H, s), 6.97-7.05 (2H, m), 7.05-7.13 (1H, m) 145ESI+: 464 146 ESI+: 297 147 ESI+: 341 148 ESI+: 422 149 ESI+: 352 150ESI+: 414 151 ESI+: 400 152 ESI+: 436 153 ESI+: 436 154 ESI+: 489

TABLE 126 Ex Data 155 ESI+: 487 156 ESI+: 374 157 ESI+: 388 158 ESI+:400 159 ESI+: 402 160 ESI+: 402 161 ESI+: 442 162 ESI+: 421 163 ESI+:449 164 ESI+: 403 165 ESI+: 431 166 ESI+: 443 167 ESI+: 529 168 ESI+:555 169 ESI+: 445 170 ESI+: 458 171 ESI+: 466 172 ESI+: 493 173 ESI+:371 174 ESI+: 362 175 ESI+: 358 176 ESI+: 371 177 ESI+: 385 178 ESI+:359 179 ESI+: 341 180 ESI+: 431 181 ESI+: 405 182 ESI+: 458 183 ESI+:458 NMR-DMSO-d₆: 1.76-1.92 (4H, m), 2.66-2.78 (2H, m), 2.87-2.98 (1H,m), 3.24 (3H, s), 3.50-3.60 (2H, m), 3.72-3.80 (2H, m), 4.10-4.18 (2H,m), 4.24 (1H, s), 4.25-4.31 (1H, m), 5.10 (2H, s), 7.13-7.21 (1H, m),7.25-7.32 (1H, m), 7.32-7.40 (1H, m), 8.22 (2H, s) 184 ESI+: 458

TABLE 127 Ex Data 185 ESI+: 458 186 ESI+: 374 187 ESI+: 374 188 ESI+:474 189 ESI+: 474 190 ESI+: 474 191 ESI+: 380 192 ESI+: 473 193 ESI+:473 194 ESI+: 420 195 ESI+: 483 196 ESI+: 483 197 ESI+: 364 198 ESI+:320 199 ESI+: 390 200 ESI+: 431 201 ESI+: 363 202 ESI+: 461 203 ESI+:460 204 ESI+: 325 205 ESI+: 408 206 ESI+: 406 207 ESI+: 490 208 ESI+:422 209 ESI+: 420 210 ESI+: 383 211 ESI+: 403 212 ESI+: 453 213 ESI+:467 214 ESI+: 433 215 ESI+: 447 216 ESI+: 448 217 ESI+: 450

TABLE 128 Ex Data 218 ESI+: 450 219 ESI+: 409 220 ESI+: 436 221 ESI+:409 222 ESI+: 422 223 ESI+: 381 224 ESI+: 407 225 ESI+: 408 226 ESI+:458 227 ESI+: 478 228 ESI+: 422 229 ESI+: 462 230 ESI+: 388 231 ESI+:388 232 ESI+: 360 233 ESI+: 374 234 ESI+: 374 235 ESI+: 402 236 ESI+:416 237 ESI+: 374 NMR-DMSO-d₆: 2.39 (3H, s), 3.84-3.92 (2H, m), 4.21(1H, s), 4.40-4.48 (2H, m), 5.03 (2H, s), 5.12-5.21 (1H, m), 6.56-6.64(1H, m), 6.75-6.82 (1H, m), 6.98-7.04 (1H, m), 7.13-7.22 (2H, m),8.02-8.08 (1H, m) 238 ESI+: 388 239 ESI+: 445 240 ESI+: 514 241 ESI+:460 NMR-DMSO-d₆: 2.63 (2H, t, J = 6.7 Hz), 3.24 (3H, s), 3.57-3.60 (6H,m), 3.76-3.85 (4H, m), 5.14 (2H, s), 7.29 (1H, t, J = 7.6 Hz), 7.41-7.45(1H, m), 7.50-7.55 (1H, m), 8.59-8.60 (2H, m) 242 ESI+: 460 243 ESI+:390

TABLE 129 Ex Data 244 ESI+: 374 NMR-DMSO-d₆: 3.67-3.70 (4H, m),3.74-3.78 (4H, m), 4.40 (2H, d, J = 5.7 Hz), 7.26 (1H, t, J = 7.6 Hz),7.31- 7.35 (1H, m), 7.44-7.48 (1H, m), 7.58-7.59 (2H, m) 245 ESI+: 382246 ESI+: 362 247 ESI+: 375 248 ESI+: 402 249 ESI+: 393 250 ESI+: 458251 ESI+: 389 252 ESI+: 405 253 ESI+: 418 254 ESI+: 492 255 ESI+: 459256 ESI+: 464 257 ESI+: 459 258 ESI+: 423 259 ESI+: 423 260 ESI+: 486261 ESI+: 486 262 ESI+: 458 263 ESI+: 488 264 ESI+: 487 265 ESI+: 487266 ESI+: 474 267 ESI+: 496 268 ESI+: 429 269 ESI+: 455 270 ESI+: 410271 ESI+: 412 272 ESI+: 422 273 ESI+: 422 274 ESI+: 436 275 ESI+: 394

TABLE 130 Ex Data 276 ESI+: 431 277 ESI+: 431 278 ESI+: 450 279 ESI+:476 280 ESI+: 410 281 ESI+: 436 282 ESI+: 461 283 ESI+: 422 284 ESI+:396 285 ESI+: 422 286 ESI+: 382 287 ESI+: 473 288 ESI+: 381 289 ESI+:408 290 ESI+: 428 291 ESI+: 394 292 ESI+: 408 293 ESI+: 373 NMR-DMSO-d₆:3.15-3.17 (4H, m), 3.35-3.37 (4H, m), 5.07 (2H, s), 7.01-7.14 (3H, m),7.24 (1H, dd, J = 4.6, 8.4 Hz), 7.37-7.40 (1H, m), 8.03 (1H, dd, J =1.3, 4.6 Hz), 8.36 (1H, d, J = 2.8 Hz) 294 ESI+: 373 295 ESI+: 387NMR-DMSO-d₆: 2.38 (3H, s), 3.09-3.14 (4H, m), 3.52-3.57 (4H, m), 5.01(2H, s), 6.80-6.85 (1H, m), 6.86-6.88 (1H, m), 7.00-7.05 (2H, m),7.08-7.13 (1H, m), 8.10 (1H, d, J = 6.1 Hz) 296 ESI+: 387 297 ESI+: 527298 ESI+: 435 299 ESI+: 387 300 ESI+: 387 NMR-DMSO-d₆: 2.37 (3H, s),3.14-3.17 (4H, m), 3.28-3.30 (4H, m), 5.06 (2H, s), 7.01-7.14 (4H, m),7.31 (1H, dd, J = 3.0, 8.5 Hz), 8.21 (1H, d, J = 2.9 Hz) 301 ESI+: 379302 ESI+: 387

TABLE 131 Ex Data 303 ESI+: 430 304 ESI+: 387 305 ESI+: 374 306 ESI+:401 307 ESI+: 398 308 ESI+: 400 309 ESI+: 370 310 ESI+: 384 311 ESI+:372 312 ESI+: 386 313 ESI+: 388 314 ESI+: 374 315 ESI+: 473 316 ESI+:459 NMR-DMSO-d₆: 3.20-3.29 (8H, m), 3.30-3.39 (3H, m), 3.88-3.98 (2H,m), 4.28-4.37 (3H, m), 5.29 (2H, s), 7.09-7.22 (3H, m), 8.48 (2H, s) 317ESI+: 457 318 ESI+: 509 319 ESI+: 357 NMR-DMSO-d₆: 3.67-3.70 (4H, m),3.74-3.77 (4H, m), 5.09 (2H, s), 7.33 (1H, d, J = 7.6 Hz), 7.44 (1H, dd,J = 7.6, 7.6 Hz), 7.58 (1H, d, J = 7.6 Hz), 7.62 (1H, s), 8.71 (2H, s)320 ESI+: 355 321 ESI+: 370 322 ESI+: 356 NMR-DMSO-d₆: 3.64-3.71 (4H,m), 3.72-3.78 (4H, m), 4.02 (1H, s), 4.27-4.38 (2H, m), 7.21-7.29 (1H,m), 7.35-7.43 (1H, m), 7.46-7.57 (2H, m), 8.70 (2H, s) 323 ESI+: 354 324FAB+: 446 325 ESI+: 500 326 FAB+: 529 327 ESI+: 417 328 ESI+: 417 329ESI+: 489

TABLE 132 Ex Data 330 ESI+: 412 331 ESI+: 444 332 ESI+: 398 333 ESI+:443 334 ESI+: 447 335 ESI+: 522 NMR-DMSO-d₆: 2.51-2.59 (2H, m),2.77-2.86 (2H, m), 3.42-3.60 (8H, m), 7.30-7.40 (3H, m), 7.50-7.60 (3H,m), 7.61-7.68 (1H, m), 8.65-8.70 (2H, m) 336 ESI+: 489 337 ESI+: 490 338ESI+: 431 NMR-DMSO-d₆: 1.09-1.20 (2H, m), 1.75-1.78 (2H, m), 1.93-2.04(1H, m), 2.20 (2H, d, J = 6.9 Hz), 2.92-2.99 (2H, m), 4.67-4.72 (2H, m),4.84 and 5.35 (2H, s and s), 7.28-7.35 (1H, m), 7.48-7.62 (2H, m),8.55-8.56 (2H, m) 339 ESI+: 446 340 ESI+: 422 341 ESI+: 422 342 ESI+:489 343 ESI+: 433 344 ESI+: 459 NMR-DMSO-d₆: 1.00-1.11 (2H, m),1.21-1.26 (2H, m), 1.51-1.59 (3H, m), 1.72-1.76 (2H, m), 2.21 (2H, t, J= 7.3 Hz), 2.87-2.94 (2H, m), 4.68-4.73 (2H, m), 5.11 (2H, s), 7.27 (1H,dd, J = 7.6, 7.6 Hz), 7.38-7.42 (1H, m), 7.48-7.52 (1H, m), 8.53-8.54(2H, m) 345 ESI+: 389 346 ESI+: 385 347 ESI+: 384 348 ESI+: 340 349ESI+: 439 350 ESI+: 389 351 ESI+: 432 352 FAB+: 439 353 ESI+: 384

TABLE 133 Ex Data 354 ESI+: 359 355 ESI+: 385 356 ESI+: 399 357 ESI+:413 358 ESI+: 433 359 ESI+: 377 360 ESI+: 377 361 ESI+: 359 362 ESI+:373 363 ESI+: 371 364 ESI+: 333 365 ESI+: 403 NMR-DMSO-d₆: 1.37-1.52(2H, m), 1.85-1.97 (2H, m), 3.29 (3H, s), 3.40-3.52 (3H, m), 4.16-4.27(3H, m), 5.11 (2H, s), 7.23-7.32 (1H, m), 7.36-7.43 (1H, m), 7.46-7.54(1H, m), 8.52-8.57 (2H, m) 366 ESI+: 373 367 ESI+: 391 368 ESI+: 458 369ESI+: 391 370 ESI+: 389 371 ESI+: 375 372 ESI+: 489 373 ESI+: 355 374ESI+: 375 375 ESI+: 528 376 ESI+: 557 377 APCI/ESI+: 459 378 APCI/ESI+:526 379 APCI/ESI+: 526 380 APCI/ESI+: 517 381 ESI+: 579 382 ESI+: 517383 ESI+: 517 384 ESI+: 580

TABLE 134 Ex Data 385 ESI+: 459 386 ESI+: 474 387 ESI+: 461 388 ESI+:487 389 ESI+: 431 390 ESI+: 431 391 ESI+: 472 392 APCI/ESI+: 457 393APCI/ESI+: 471 394 APCI/ESI+: 475 395 APCI/ESI+: 550 396 ESI+: 493 397ESI+: 523, 525 398 ESI+: 426 399 ESI+: 330 400 ESI+: 342 401 ESI+: 343402 ESI+: 344 403 ESI+: 344 404 ESI+: 356 405 ESI+: 356 406 ESI+: 356407 ESI+: 357 408 ESI+: 357 409 ESI+: 358 410 ESI+: 369 411 ESI+: 370412 ESI+: 370 413 ESI+: 370 414 ESI+: 370 415 ESI+: 370 416 ESI+: 370417 ESI+: 371

TABLE 135 Ex Data 418 ESI+: 371 419 ESI+: 371 420 ESI+: 371 421 ESI+:372 422 ESI+: 372 423 ESI+: 372 424 ESI+: 374 425 ESI+: 376 426 ESI+:383 427 ESI+: 383 428 ESI+: 383 429 ESI+: 383 430 ESI+: 383 431 ESI+:384 432 ESI+: 384 433 ESI+: 384 434 ESI+: 384 435 ESI+: 384 436 ESI+:384 437 ESI+: 384 438 ESI+: 384 439 ESI+: 384 440 ESI+: 385 441 ESI+:385 442 ESI+: 386 443 ESI+: 386 444 ESI+: 386 445 ESI+: 386 446 ESI+:386 447 ESI+: 388 448 ESI+: 392 449 ESI+: 393 450 ESI+: 397

TABLE 136 Ex Data 451 ESI+: 397 452 ESI+: 397 453 ESI+: 397 454 ESI+:397 455 ESI+: 397 456 ESI+: 398 457 ESI+: 398 458 ESI+: 398 459 ESI+:398 460 ESI+: 398 461 ESI+: 398 462 ESI+: 398 463 ESI+: 398 464 ESI+:398 465 ESI+: 398 466 ESI+: 399 467 ESI+: 399 468 ESI+: 399 469 ESI+:399 470 ESI+: 399 471 ESI+: 399 472 ESI+: 406 473 ESI+: 407 474 ESI+:411 475 ESI+: 392 476 ESI+: 406 477 ESI+: 406 478 ESI+: 419 479 ESI+:419 480 ESI+: 419 481 ESI+: 433 482 ESI+: 447 483 ESI+: 455

TABLE 137 Ex Data 484 ESI+: 406 485 ESI+: 433 486 ESI+: 447 487 ESI+:454 488 ESI+: 461 489 ESI+: 469 490 ESI+: 475 491 ESI+: 505 492 ESI+:505 493 ESI+: 505 494 ESI+: 420 495 ESI+: 433 496 ESI+: 466 497 ESI+:433 498 ESI+: 377 499 ESI+: 422 500 ESI+: 416 501 ESI+: 416 502 ESI+:417 503 ESI+: 430 504 ESI+: 427 505 ESI+: 428 506 ESI+: 444 507 ESI+:380 508 ESI+: 397 509 ESI+: 391 510 ESI+: 392 511 ESI+: 430 512 ESI+:430 513 ESI+: 393 514 ESI+: 482 515 ESI+: 447 516 ESI+: 417

TABLE 138 Ex Data 517 ESI+: 417 518 ESI+: 417 519 ESI+: 475 520 ESI+:480 521 ESI+: 431 522 ESI+: 475 523 ESI+: 475 524 ESI+: 475 525 ESI+:486 526 ESI+: 449 527 ESI+: 487 528 ESI+: 460 529 ESI+: 495 530 ESI+:411 531 ESI+: 411 532 ESI+: 413 533 ESI+: 415 534 ESI+: 418 535 ESI+:418 536 ESI+: 421 537 ESI+: 423 538 ESI+: 426 539 ESI+: 427 540 ESI+:433 541 ESI+: 435 542 ESI+: 438 543 ESI+: 439 544 ESI+: 441 545 ESI+:441 546 ESI+: 441 547 ESI+: 441 548 ESI+: 447 549 ESI+: 453 550 ESI+:461

TABLE 139 Ex Data 551 ESI+: 422 NMR-DMSO-d₆: 1.02 (3H, t, J = 7.4 Hz),1.27-1.50 (2H, m), 1.77-1.93 (2H, m), 2.35 (2H, q, J = 7.4 Hz), 3.03(1H, t, J = 9.9 Hz), 3.19 (1H, t, J = 9.9 Hz), 3.57-3.80 (4H, m),3.91-4.04 (1H, m), 4.19-4.27 (3H, m), 4.54-4.63 (1H, m), 5.05 (2H, s),6.57 (1H, t, J = 8.0 Hz), 6.79 (1H, t, J = 6.4 Hz), 7.03 (1H, t, J = 7.8Hz). 552 ESI+: 374 NMR-DMSO-d₆: 2.40 (3H, s), 3.82-3.89 (2H, m), 4.21(2H, s), 4.37-4.44 (2H, m), 5.03 (2H, s), 5.13-5.20 (1H, m), 6.55-6.61(1H, m), 6.74-6.81 (1H, m), 7.01 (1H, t, J = 7.8 Hz), 7.17-7.27 (2H, m),8.12 (1H, d, J = 2.7 Hz). 553 ESI+: 404 NMR-DMSO-d₆: 3.28 (3H, s),3.84-3.91 (2H, m), 4.21 (2H, s), 4.38-4.45 (4H, m), 5.02 (2H, s),5.18-5.24 (1H, m), 6.55-6.62 (1H, m), 6.75-6.80 (1H, m), 7.01 (1H, t, J= 7.8 Hz), 7.34-7.37 (2H, m), 8.19-8.22 (1H, m). 554 ESI+: 417NMR-DMSO-d₆: 3.13-3.20 (4H, m), 3.31 (3H, s), 3.32-3.39 (4H, m), 4.21(2H, s), 4.39 (2H, s), 5.07 (2H, s), 7.00-7.15 (3H, m), 7.26 (1H, d, J =7.6 Hz), 7.37-7.42 (1H, m), 8.29 (1H, d, J = 2.8 Hz). 555 ESI+: 402NMR-DMSO-d₆: 2.41 (6H, s), 3.72-3.78 (2H, m), 4.12-4.19 (2H, m), 4.20(2H, s), 4.45 (2H, s), 4.46-4.51 (1H, m), 5.01 (2H, s), 6.50-6.56 (1H,m), 6.71-6.77 (1H, m), 6.95-7.02 (3H, m). 556 ESI+: 412 NMR-DMSO-d₆:3.12-3.20 (4H, m), 3.37-3.45 (4H, m), 4.06 (1H, s), 5.03 (2H, s), 6.77(1H, d, J = 2.2 Hz), 6.94-7.14 (4H, m), 7.42 (1H, d, J = 1.4 Hz), 7.69(1H, d, J = 0.8 Hz), 8.37 (1H, d, J = 7.6 Hz). 557 ESI+: 390NMR-DMSO-d₆: 3.39 (3H, s), 3.79-3.86 (2H, m), 4.20 (2H, s), 4.29-4.37(2H, m), 4.87-4.94 (1H, m), 5.02 (2H, s), 6.35-6.40 (1H, m), 6.57 (1H,t, J = 8.0 Hz), 6.77 (1H, t, J = 6.4 Hz), 7.01 (1H, t, J = 7.8 Hz),7.29-7.35 (2H, m). 558 ESI+: 417 NMR-DMSO-d₆: 3.13-3.19 (4H, m), 3.30(3H, s), 3.33-3.40 (4H, m), 4.21 (2H, s), 4.41 (2H, s), 5.08 (2H, s),7.01-7.15 (3H, m), 7.31 (1H, s), 7.99 (1H, d, J = 1.4 Hz), 8.29 (1H, d,J = 2.7 Hz).

TABLE 140 Ex Data 559 ESI+: 392 NMR-DMSO-d₆: 0.81-1.09 (2H, m),1.59-1.75 (3H, m), 1.98 (3H, s), 2.39-2.52 (2H, m), 2.93-3.03 (1H, m),3.58-3.65 (2H, m), 3.77-3.85 (1H, m), 3.93-4.01 (2H, m), 4.21 (2H, s),4.34-4.42 (1H, m), 5.01 (2H, s), 6.46-6.52 (1H, m), 6.69-6.74 (1H, m),6.97 (1H, t, J = 7.8 Hz). 560 ESI+: 406 NMR-DMSO-d₆: 0.82-1.04 (5H, m),1.59-1.78 (3H, m), 2.29 (2H, q, J = 7.4 Hz), 2.37-2.49 (2H, m),2.89-2.99 (1H, m), 3.57-3.65 (2H, m), 3.79-3.89 (1H, m), 3.93-4.00 (2H,m), 4.18 (1H, s), 4.34-4.43 (1H, m), 4.98 (2H, s), 6.44-6.52 (1H, m),6.67-6.74 (1H, m), 6.97 (1H, t, J = 7.8 Hz). 561 ESI+: 418 NMR-DMSO-d₆:0.63-0.75 (4H, m), 0.83-1.07 (2H, m), 1.56-1.80 (3H, m), 1.89-2.00 (1H,m), 2.38-2.59 (2H, m), 2.99-3.11 (1H, m), 3.57-3.65 (2H, m), 3.92-4.01(2H, m), 4.18 (1H, s), 4.19-4.22 (2H, m), 4.98 (2H, s), 6.44-6.52 (1H,m), 6.67-6.73 (1H, m), 6.97 (1H, t, J = 7.7 Hz). 562 ESI+: 422NMR-DMSO-d₆: 0.85-1.09 (2H, m), 1.62-1.76 (3H, m), 2.38-2.59 (2H, m),2.87-2.97 (1H, m), 3.27 (3H, s), 3.58-3.65 (2H, m), 3.72-3.80 (1H, m),3.93-4.11 (4H, m), 4.20 (2H, m), 4.30-4.38 (1H, m), 5.00 (2H, s),6.45-6.52 (1H, m), 6.68-6.74 (1H, m), 6.97 (1H, t, J = 7.7 Hz). 563ESI+: 436 NMR-DMSO-d₆: 0.83-1.05 (2H, m), 1.60-1.75 (3H, m), 2.37-2.58(4H, m), 2.90-3.00 (1H, m), 3.22 (3H, s), 3.53 (2H, t, J = 6.4 Hz),3.58-3.65 (2H, m), 3.85-3.92 (1H, m), 3.93-4.01 (2H, m), 4.18 (1H, s),4.34-4.42 (1H, m), 4.98 (2H, s), 6.45-6.50 (1H, m), 6.67-6.73 (1H, m),6.97 (1H, t, J = 7.8 Hz). 564 ESI+: 428 NMR-DMSO-d₆: 1.08-1.19 (2H, m),1.53-1.64 (1H, m), 1.70-1.80 (2H, m), 2.41-2.51 (2H, m), 2.62-2.72 (2H,m), 2.84 (3H, s), 3.53-3.65 (4H, m), 3.94-4.01 (2H, m), 4.18 (1H, s),4.98 (1H, s), 6.44-6.52 (1H, m), 6.67-6.73 (1H, m), 6.97 (1H, t, J = 7.8Hz). 565 ESI+: 447 NMR-DMSO-d₆: 3.05-3.12 (4H, m), 3.28 (3H, s),3.41-3.47 (4H, m), 3.59-3.63 (2H, m), 4.18 (1H, s), 4.28-4.33 (2H, m),5.04 (2H, s), 6.19 (1H, d, J = 2.2 Hz), 6.59-6.63 (1H, m), 6.98-713 (3H,m), 7.81 (1H, d, J = 6.1 Hz).

TABLE 141 Ex Data 566 ESI+: 417 NMR-DMSO-d₆: 3.10-3.15 (4H, m), 3.36(3H, s), 3.49-3.55 (4H, m), 4.15 (2H, s), 4.39 (2H, s), 5.04 (2H, s),6.82-6.86 (1H, m), 6.91 (1H, d, J = 2.4 Hz), 7.00-7.14 (3H, m), 8.15(1H, d, J = 6.1 Hz). 567 ESI+: 392 NMR-DMSO-d6: 0.81-1.09 (2H, m),1.59-1.75 (3H, m), 1.98 (3H, s), 2.39-2.52 (2H, m), 2.93-3.03 (1H, m),3.58-3.65 (2H, m), 3.77-3.85 (1H, m), 3.93-4.01 (2H, m), 4.21 (2H, s),4.34-4.42 (1H, m), 5.01 (2H, s), 6.46-6.52 (1H, m), 6.69-6.74 (1H, m),6.97 (1H, t, J = 7.8 Hz).

The compounds of Preparation Examples shown in the tables below wereprepared using the respective corresponding starting materials in thesame manner as the methods of Preparation Examples above. Thestructures, the preparation methods, and the physicochemical data forthe compounds of Preparation Examples are shown in the tables below.

TABLE 142 Rf Syn Structure 843 R12 

844 R845

845 R845

846 R70 

847 R847

848 R806

849 R806

850 R806

851 R807

852 R809

853 R853

854 R853

855 R855

856 R855

TABLE 143 Rf Syn Structure 857 R857

858 R859

859 R859

860 R860

861 R228

862 R228

863 R228

864 R228

865 R228

866 R228

867 R228

868 R228

TABLE 144 Rf Syn Structure 869 R285

870 R285

871 R285

872 R285

873 R285

874 R285

875 R285

876 R285

877 R285

878 R285

879 R285

880 R285

881 R285

882 R285

TABLE 145 Rf Syn Structure 883 R285

884 R285

885 R285

886 R285

887 R285

888 R285

889 R285

890 R285

891 R285

892 R285

893 R893

894 R894

895 R894

896 R821

897 R821

898 R821

TABLE 146 Rf Syn Structure 899 R821

900 R821

901 R821

902 R821

903 R821

904 R821

905 R821

906 R821

907 R821

908 R821

909 R821

910 R821

911 R343

912 R343

913 R376

914 R376

TABLE 147 Rf Syn Structure 915 R376

916 R376

917 R376

918 R376

919 R478

920 R518

921 R574

922 R922

923 R922

924 R581

925 R581

926 R926

927 R926

928 R584

929 R584

930 R603

TABLE 148 Rf Syn Structure 931 R603

932 R663

933 R677

934 R680

935 R686

936 R712

937 R712

938 R938

939 R758

940 R758

941 R772

TABLE 149 Rf Data 843 ESI+: 164 844 ESI+: 430 845 ESI+: 416 846APCI/ESI+: 317 847 ESI+: 265 848 ESI+: 156, 158 849 ESI+: 168, 170 850ESI+: 158, 160 851 ESI+: 304 852 ESI+: 232 853 ESI+: 318 854 ESI+: 332855 ESI+: 190 856 ESI+: 218 857 NMR-CDCl₃: 1.44 (9H, s), 1.51 (3H, s),3.81-3.87 (4H, m) 858 APCI/ESI+: 354 859 APCI/ESI+: 368 860 ESI+: 150861 ESI+: 474 862 ESI+: 403 863 ESI+: 441 864 ESI+: 455 865 APCI/ESI+:455 866 APCI/ESI+: 387 867 ESI+: 398 868 APCI/ESI+: 401 869 ESI+: 303870 ESI+: 303 871 ESI+: 331 872 ESI+: 331 873 ESI+: 331 874 ESI+: 303875 ESI+: 317

TABLE 150 Rf Data 876 ESI+: 329 877 ESI+: 319 878 ESI+: 347 879 ESI+:372 880 ESI+: 386 881 ESI+: 402 882 ESI+: 416 883 ESI+: 333 884 ESI+:347 885 ESI+: 314 886 ESI+: 342 887 ESI+: 317 888 ESI+: 317 889 ESI+:356 890 ESI+: 356 891 ESI+: 317 892 ESI+: 356 893 ESI+: 326 894 ESI+:374 895 ESI+: 388 896 ESI+: 205 897 ESI+: 179 898 ESI+: 179 899 ESI+:207 900 ESI+: 207 901 ESI+: 179 902 ESI+: 207 903 ESI+: 193 904 ESI+:195 905 ESI+: 223 906 ESI+: 193 907 ESI+: 193 908 ESI+: 232 909 ESI+:232

TABLE 151 Rf Data 910 ESI+: 193 911 ESI+: 400 912 ESI+: 428 913 ESI+:360 914 ESI+: 289 915 ESI+: 327 916 ESI+: 341 917 APCI/ESI+: 273 918APCI/ESI+: 287 919 NMR-CDCl₃: 1.80 (1H, br), 3.26 (2H, t, J = 5 Hz),3.73 (2H, s), 3.77 (2H, t, J = 5 920 APCI/ESI+: 341 921 ESI+: 404 922ESI+: 209 923 ESI+: 223 924 APCI/ESI+: 247 925 APCI/ESI+: 261 926 ESI+:303 927 ESI+: 361 928 ESI+: 140 929 ESI+: 138 930 APCI/ESI+: 249 931APCI/ESI+: 263 932 ESI+: 166 933 ESI+: 336 934 ESI+: 335 935 ESI+: 337936 APCI/ESI+: 149 937 APCI/ESI+: 163 938 ESI+: 319 939 ESI+: 388 940ESI+: 402 941 ESI+: 369

The compounds of Examples shown in the tables below were prepared usingthe respective corresponding starting materials in the same manner asthe methods of Examples above. The structures, the preparation methods,and the physicochemical data for the compounds of Examples are shown inthe tables below.

TABLE 152 Ex Syn Structure 568 568

569  3

570 112

571 112

572 112

573 112

574 112

575 112

576 112

577 112

578 112

579 112

580 112

581 112

582 112

583 112

TABLE 153 Ex Syn Structure 584 112

585 112

586 112

587 588

588 588

589 112

590 112

591 112

592 112

593 112

594 112

595 112

596 112

597 112

598 112

599 112

TABLE 154 Ex Syn Structure 600 112

601 112

602 112

603 112

604 112

605 112

606 112

607 112

608 112

609 112

610 112

611 112

612 112

613 112

TABLE 155 Ex Syn Structure 614 112

615 615

616 615

617  3

618 112

619 619

620 619

621 619

622 619

623 619

TABLE 156 Ex Data 568 ESI+: 389 569 APCI/ESI+: 426 570 APCI/ESI+: 358571 APCI/ESI+: 372 572 ESI+: 388 573 ESI+: 388 574 ESI+: 416 575 ESI+:416 576 ESI+: 416 577 ESI+: 388 578 ESI+: 403 579 ESI+: 374 580 ESI+:402 581 ESI+: 414 582 ESI+: 404 583 ESI+: 432 584 ESI+: 412 585 ESI+:457 586 ESI+: 471 587 ESI+: 487 588 ESI+: 501 589 ESI+: 485 590 ESI+:513 591 ESI+: 418 592 ESI+: 432 593 ESI+: 459 594 ESI+: 473 595 ESI+:487 596 ESI+: 501 597 ESI+: 473 598 ESI+: 487 599 ESI+: 390 600 ESI+:426

TABLE 157 Ex Data 601 ESI+: 417 602 ESI+: 388 603 ESI+: 404 604 ESI+:399 605 ESI+: 427 606 ESI+: 402 607 ESI+: 402 608 ESI+: 441 609 ESI+:441 610 ESI+: 402 611 ESI+: 441 612 ESI+: 422 613 ESI+: 454 614 ESI+:421 615 ESI+: 376 616 ESI+: 390 617 ESI+: 445 618 ESI+: 420 619 ESI+:375 DSC endothermic onset temperature: 197.4° C. 620 ESI+: 359 DSCendothermic onset temperature: 184.7° C. 621 ESI+: 387 DSC endothermiconset temperature: 173.0° C. 622 ESI+: 417 DSC endothermic onsettemperature: 207.8° C. 623 ESI+: 445 DSC endothermic onset temperature:204.0° C.

INDUSTRIAL APPLICABILITY

The compound of formula (I) or a salt thereof has a VAP-1 inhibitoryaction, and can be used as an agent for preventing and/or treating VAP-1related diseases.

The invention claimed is:
 1. A compound of formula (I):

wherein A is

Q¹ is a single bond or CR^(Q11)R^(Q12), Q³ is CR^(Q31) or N, Q⁵ is asingle bond or (CR^(Q51)R^(Q52))_(a), Q⁶ is CR^(Q61) or N, in whicheither one of Q³ and Q⁶ is N, R^(Q11), R^(Q12), R^(Q21), R^(Q22),R^(Q31), R^(Q41), R^(Q42), R^(Q51), R^(Q52) and R^(Q61) are the same asor different from each other, and are H, OH, or lower alkyl, or R^(Q51)and R^(Q61) may be combined with each other to form a new bond, orR^(Q11) and R^(Q12) may be combined with each other to form oxo (═O), ais 1, or 2, R¹, R², R³ and R⁴ are the same as or different from eachother, and are H, halogen, or lower alkyl, E is a single bond, G is asingle bond, J is a single bond, L is O or NH, N(lower alkyl), U is asingle bond or O, V is a single bond or lower alkylene which may besubstituted with OH, O-(lower alkyl), or oxo (═O), W is a single bond, Xis H, OH, NH₂, lower alkyl which may be substituted with halogen,O-(lower alkyl which may be substituted with OH), NH(lower alkyl whichmay be substituted with oxo (═O)), N(lower alkyl which may besubstituted with O-(lower alkyl) or oxo (═O))₂, NH—SO₂-(lower alkyl),N(lower alkyl)-SO₂-(lower alkyl), cycloalkyl which may be substitutedwith group(s) selected from Group G^(XA1) below, O-(cycloalkyl),cycloalkenyl which may be substituted with group(s) selected from GroupG^(XA1) below, aryl which may be substituted with group(s) selected fromGroup G^(XA1) below, O-(aryl which may be substituted with O-(loweralkyl)), or a hetero ring group which may be substituted with group(s)selected from Group G^(XA1) below, and G^(XA1) is i) halogen, ii) OH,iii) lower alkyl which may be substituted with group(s) selected fromthe group consisting of halogen; OH; O-(lower alkyl which may besubstituted with OH, aryl, O-(lower alkyl), or oxo (═O)); NH₂; NH(loweralkyl which may be substituted with OH); N(lower alkyl)₂;NH(cycloalkyl); NH(hetero ring group); cycloalkyl which may besubstituted with OH; aryl which may be substituted with O-(lower alkyl),COOH, or COO-(lower alkyl which may be substituted with aryl); heteroring group(s) which may be substituted with O-(lower alkyl), oxo (═O),NH(lower alkyl which may be substituted with oxo (═O)), or lower alkyl;and oxo (═O), iv) O-(lower alkyl which may be substituted with OH,O-(lower alkyl), aryl, hetero ring group(s) (in which the hetero ringgroup may be substituted with lower alkyl which may be substituted withcycloalkyl or oxo (═O)), or oxo (═O)), v) NH-(lower alkyl which may besubstituted with O-(lower alkyl) or oxo (═O)), vi) N(lower alkyl whichmay be substituted with oxo (═O))₂, vii) NH-(aryl which may besubstituted with COOH or COO-(lower alkyl)), viii) cycloalkyl which maybe substituted with group(s) selected from the group consisting of loweralkyl which may be substituted with OH; COOH; and COO-(lower alkyl), ix)aryl which may be substituted with group(s) selected from the groupconsisting of halogen; lower alkyl (in which the lower alkyl may besubstituted with COOH or COO-(lower alkyl)); O-(lower alkyl); COOH; andCOO-(lower alkyl), x) hetero ring group(s) which may be substituted withgroup(s) selected from the group consisting of OH; halogen; lower alkylwhich may be substituted with OH, O-(lower alkyl), or oxo (═O); O-(loweralkyl which may be substituted with O-(lower alkyl)); and oxo (═O), xi)O-(hetero ring group), xii) SO₂-(lower alkyl which may be substitutedwith O-(lower alkyl)), xiii) SO₂-(cycloalkyl), xiv) SO₂-(aryl), xv)NHSO₂-(lower alkyl), or xvi) oxo (═O); or a salt of said compound. 2.The compound or a salt of said compound according to claim 1, wherein Ais

Q¹ is a single bond or CR^(Q11)R^(Q12), Q³ is CR^(Q31) or N, Q⁵ is asingle bond or (CR^(Q51)R^(Q52))_(a), Q⁶ is CR^(Q61) or N, in whicheither one of Q³ and Q⁶ is N, R^(Q11), R^(Q12), R^(Q21), R^(Q22),R^(Q31), R^(Q41), R^(Q42), R^(Q51), R^(Q52) and R^(Q61) are the same asor different from each other, and are H, or R^(Q51) and R^(Q61) may becombined with each other to form a new bond, or R^(Q11) and R^(Q12) maybe combined with each other to form oxo (═O), and a is 1, R¹, R², R³ andR⁴ are the same as or different from each other, and are H or halogen, Lis O, X is H, lower alkyl, O-(lower alkyl), cycloalkyl which may besubstituted with group(s) selected from Group G^(XC1) below,cycloalkenyl which may be substituted with group(s) selected from GroupG^(XC1) below, aryl which may be substituted with group(s) selected fromGroup G^(XC1) below, or a hetero ring group which may be substitutedwith group(s) selected from Group G^(XC1) below, and G^(XC1) is i) OH,ii) lower alkyl which may be substituted with group(s) selected from thegroup consisting of OH; O-(lower alkyl which may be substituted witharyl); N(lower alkyl)₂; cycloalkyl; hetero ring group(s) which may besubstituted with lower alkyl; and oxo (═O), iii) O-(lower alkyl whichmay be substituted with O-(lower alkyl), aryl, hetero ring group(s) (inwhich the hetero ring group may be substituted with lower alkyl whichmay be substituted with cycloalkyl or oxo (═O)), or oxo (═O)), iv)NH-(lower alkyl which may be substituted with O-(lower alkyl) or oxo(═O)), v) cycloalkyl, vi) hetero ring group(s) which may be substitutedwith group(s) selected from the group consisting of OH; halogen; loweralkyl which may be substituted with OH, O-(lower alkyl), or oxo (═O);O-(lower alkyl which may be substituted with O-(lower alkyl)); and oxo(═O), vii) O-(hetero ring group), viii) SO₂-(lower alkyl), ix)SO₂-(cycloalkyl), or x) oxo (═O); or a salt of said compound.
 3. Thecompound or a salt of said compound according to claim 2, wherein X isH, lower alkyl, or O-(lower alkyl), or X is

T¹ is a single bond, CR^(T11)R^(T12), or NR^(T13), T³ is CR^(T31) or N,T⁵ is a single bond or CR^(T51)R^(T52), T⁶ is a single bond,CR^(T61)R^(T62), O, or NR^(T63), R^(T11), R^(T12), R^(T13), R^(T21),R^(T22), R^(T31), R^(T41), R^(T42), R^(T51), R^(T52), R^(T61), R^(T62)and R^(T63) are the same as or different from each other, and are H, OH,lower alkyl which may be substituted with group(s) selected from thegroup consisting of O-(lower alkyl which may be substituted with aryl);N(lower alkyl)₂; cycloalkyl; hetero ring group(s) which may besubstituted with lower alkyl; and oxo (═O), O-(lower alkyl which may besubstituted with aryl or oxo (═O)), a hetero ring group which may besubstituted with group(s) selected from the group consisting of loweralkyl which may be substituted with OH or oxo (═O); and oxo (═O),SO₂-(lower alkyl), or SO₂-(cycloalkyl), or R^(T21) and R^(T31), orR^(T41) and R^(T51) may be combined with each other to form a new bond,or R^(T61) and R^(T62) may be combined with each other to form oxo (═O),or X is

T¹ is CR^(T12) or N, T² is CR^(T22) or N, T⁴ is CR^(T42), or N, T⁵ isCR^(T52) or N, T⁶ is CR^(T62) or N, R^(T12), R^(T22), R^(T42), R^(T52)and R^(T62) are the same as or different from each other, and are H,lower alkyl which may be substituted with OH, O-(lower alkyl), or oxo(═O), O-(lower alkyl which may be substituted with O-(lower alkyl) orhetero ring group(s) (in which the hetero ring group may be substitutedwith lower alkyl which may be substituted with cycloalkyl or oxo (═O))),NH-(lower alkyl which may be substituted with O-(lower alkyl)),cycloalkyl, a hetero ring group which may be substituted with group(s)selected from the group consisting of OH; halogen; lower alkyl which maybe substituted with O-(lower alkyl) or oxo (═O); and O-(lower alkylwhich may be substituted with O-(lower alkyl)), or O-(hetero ringgroup), or X is thiazolyl which may be substituted with morpholinyl orNH(lower alkyl which may be substituted with oxo (═O)), benzothiazolyl,or imidazo[1,2-a]pyridyl which may be substituted with lower alkyl; or asalt of said compound.
 4. The compound or a salt of said compoundaccording to claim 3, wherein Q¹ is a single bond, Q³ is N, Q⁵ is asingle bond, Q⁶ is CR^(Q61), X is

T¹ is CR^(T11)R^(T12), or NR^(T13), T³ is CR^(T31), T⁵ isCR^(T51)R^(T52), T⁶ is CR^(T61)R^(T62), or NR^(T63), R^(T11), R^(T12),R^(T13), R^(T21), R^(T22), R^(T31), R^(T41), R^(T42), R^(T51), R^(T52),R^(T61) and R^(T62) are the same as or different from each other, andare H or lower alkyl, or R^(T61) and R^(T62) may be combined with eachother to form oxo (═O), R^(T63) is lower alkyl which may be substitutedwith group(s) selected from the group consisting of O-(lower alkyl);N(lower alkyl)₂; cycloalkyl; hetero ring group(s) which may besubstituted with lower alkyl; and oxo (═O), a monocyclic hetero ringgroup which may be substituted with group(s) selected from the groupconsisting of lower alkyl which may be substituted with OH or oxo (═O);and oxo (═O), SO₂-(lower alkyl), or SO₂-(cycloalkyl), or R^(T21) andR^(T31), or R^(T41) and R^(T51) may be combined with each other to forma new bond; or a salt of said compound.
 5. The compound or a salt ofsaid compound according to claim 4, wherein R^(T63) is lower alkyl whichmay be substituted with group(s) selected from the group consisting ofO-(lower alkyl); N(lower alkyl)₂; cycloalkyl; nitrogen-containingmonocyclic unsaturated hetero ring group(s) which may be substitutedwith lower alkyl; monocyclic saturated hetero ring group(s); and oxo(═O), a nitrogen-containing monocyclic hetero ring group which may besubstituted with group(s) selected from the group consisting of loweralkyl which may be substituted with OH or oxo (═O); and oxo (═O),SO₂-(lower alkyl), or SO₂-(cycloalkyl); or a salt of said compound. 6.The compound or a salt of said compound according to claim 5, whereinR^(T63) is lower alkyl which may be substituted with group(s) selectedfrom the group consisting of O-(lower alkyl); N(lower alkyl)₂;cyclopropyl; pyridyl which may be substituted with lower alkyl;tetrahydropyranyl; and oxo (═O), 1,2-dihydropyridyl or pyridyl, each ofwhich may be substituted with group(s) selected from the groupconsisting of lower alkyl which may be substituted with OH or oxo (═O);and oxo (═O), SO₂-(lower alkyl), or SO₂-(cyclopropyl); or a salt of saidcompound.
 7. The compound or a salt of said compound according to claim1, which is selected from the group consisting of2-fluoro-3-{3-[(6-methylpyridin-3-yl)oxy]azetidin-1-yl}benzylcarbamimidoylcarbamate,2-fluoro-3-{3-[(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)oxy]azetidin-1-yl}benzylcarbamimidoylcarbamate, and3-[3-(1-acetylpiperidin-4-yl)azetidin-1-yl]-2-fluorobenzylcarbamimidoylcarbamate, or a salt of said compound.
 8. The compound or asalt of said compound according to claim 7, which is2-fluoro-3-{3-[(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)oxy]azetidin-1-yl}benzylcarbamimidoylcarbamate or a salt of said compound.
 9. The compound or asalt of said compound according to claim 7, which is2-fluoro-3-{3-[(6-methylpyridin-3-yl)oxy]azetidin-1-yl}benzylcarbamimidoylcarbamate or a salt of said compound.
 10. The compound or asalt of said compound according to claim 7, which is3-[3-(1-acetylpiperidin-4-yl)azetidin-1-yl]-2-fluorobenzylcarbamimidoylcarbamate or a salt of said compound.
 11. A pharmaceuticalcomposition comprising the compound according to claim 7 or a salt ofsaid compound and a pharmaceutically acceptable carrier or excipient.12. A method for treating diabetic nephropathy or diabetic macular edemain a patient in need thereof, comprising administering to said patientan effective amount of the compound according to claim 7 or a salt ofsaid compound.
 13. A method for treating diabetic nephropathy in apatient in need thereof, comprising administering to said patient aneffective amount of the compound according to claim 7 or a salt of saidcompound.
 14. A method for treating diabetic macular edema in a patientin need thereof, comprising administering to said patient an effectiveamount of the compound according to claim 7 or a salt of said compound.